Antigen recognition in B cells is mediated by the B cell antigen receptor (BCR), composed of two immunoglobulin (Ig) heavy chains (HC) and two Igκ or Igλ light chains (LC). They form the BCR complex together with the associated Igα and Igβ heterodimer to transmit signals for B cell development, proliferation, survival, and activation. Each B cell expresses a BCR with a given specificity, which is acquired by a progressive rearrangement of the variable (V), joining (J) and, in case of the HC, diversity (D) gene segments of the BCR HC and LC loci in the bone marrow (BM) (reviewed in Clark et al., 2014; Herzog et al., 2009). The key enzymes that facilitate V(D)J recombination are recombination-activating gene 1 (RAG1) and RAG2 proteins (Oettinger et al., 1990; Schatz et al., 1989). V(D)J recombination is initiated at the pro-B cell stage (Rolink et al., 1999). An in-frame rearrangement at the HC genes leads to the expression of a µHC that is binding to the λ5 and VpreB components of the surrogate light chain (Karasuyama et al., 1990; Reth et al., 1985; Tsubata and Reth, 1990). Together with the Igα/β signaling subunits, these chains form the pre-BCR complex, which is first expressed on large pre-B cells. Signals from the pre-BCR and the interleukin (IL)–7 receptor (IL-7R) induce a proliferative burst that is followed by cell cycle attenuation, promoting LC V- to J-gene segment rearrangement in the small pre-B cell stage (Flemming et al., 2003; Ma et al., 2010; Mandal et al., 2009; Ochiai et al., 2012; Reth et al., 1985; Reth and Nielsen, 2014). A productive rearrangement leads to the pairing of the pre-existing HC with the newly generated LC, forming the IgM-BCR expressed first on the immature B cells in the BM (reviewed in Herzog et al., 2009; Matthias and Rolink, 2005).

LC locus opening and recombination during B cell development and receptor editing (a process changing the specificity of the BCR by secondary LC VJ-gene rearrangements) is dependent on transcription factors including Ikaros, Aiolos, interferon regulatory factor (IRF)–4, IRF-8 and E2A (Bai et al., 2007; Beck et al., 2009; Inlay et al., 2004; Johnson et al., 2008; Lazorchak et al., 2006; Lu et al., 2003; Ma et al., 2006; Ma et al., 2008; Mandal et al., 2009; Pathak et al., 2008; Quong et al., 2004; Stadhouders et al., 2014). Genetic mouse models individually lacking some of these transcription factors show impaired LC locus opening, affecting λLC expression more severely (Beck et al., 2009; Lu et al., 2003; Pathak et al., 2008; Quong et al., 2004). The activity of these transcription factors is directly or indirectly regulated by pre-BCR and BCR signaling. Mice lacking a signaling competent pre-BCR or BCR, or lacking signaling molecules downstream of the pre-BCR or BCR including the adapter protein SLP65, Bruton’s tyrosine kinase (BTK) and phospholipase Cγ2 (PLCγ2), are characterized by an altered LC expression (Bai et al., 2007; Dingjan et al., 2001; Hayashi et al., 2004; Kersseboom et al., 2006; Xu et al., 2007). Specifically, mice deficient in SLP65 show reduced LC germline transcripts especially from the Igl locus (Hayashi et al., 2004; Kersseboom et al., 2006; Stadhouders et al., 2014). Likewise, the absence of BTK, a kinase that is recruited by SLP65, severely reduces Igl germline transcripts and LC expression (Dingjan et al., 2001; Kersseboom et al., 2006; Stadhouders et al., 2014). The concurrent ablation of both SLP65 and BTK abrogates Igk and Igl germline transcription and BCR surface expression (Kersseboom et al., 2006; Stadhouders et al., 2014). PLCγ2 is recruited to SLP65, regulating the calcium signaling downstream of the pre-BCR and BCR (Hashimoto et al., 2000; Xu et al., 2007). PLCγ2-knockout (KO) mice show a strong reduction of λLC B cells and a mild reduction of Igk germline transcripts (Bai et al., 2007; Xu et al., 2007). The combined deficiency of BTK and PLCγ2 almost completely abrogated LC expression (Xu et al., 2007).

Pre-BCR signaling is important for the induction of LC VJ-gene rearrangement at both LC loci (Igk and Igl). However, the ratio between the usage of the two LCs diverges greatly among species (Sun et al., 2013) and the regulation of their differential expression is still not fully understood. The primary B cell repertoire in mice is dominated by the κLC that is roughly ten to 20 times more frequent than the λLC (McGuire and Vitetta, 1981; Sun et al., 2013). It is generally accepted that λLC B cell generation is favored when rearrangement at the Igk locus is unsuccessful, or when the immature κLC-containing BCR confers autoreactivity (Luning Prak et al., 2011; Nemazee, 2006). In the latter case, the BCR specificity is modified by receptor editing. The ratio of κ/λ LC is further impacted by the survival of developing B cells. Extending the life-span of B cell precursors by overexpression of the anti-apoptotic protein B cell lymphoma 2 (BCL2), promotes the generation of λLC B cells (Ait-Azzouzene et al., 2005; Derudder et al., 2009; Dingjan et al., 2001). In line with this, limiting B cell survival by genetically abrogating the NF-κB signaling pathway, results in mice with a reduced amount of λLC B cells (Derudder et al., 2009). Based on these observations, the generation of λLC B cells mainly depends on (i) the ability and kinetics of the LC locus opening, (ii) the life-span of developing B cells, and (iii) the efficiency of receptor editing during tolerance induction (Derudder et al., 2009).

In this study, we investigated the differential regulation of the κ- versus λLC expression. We have identified the transmembrane protein Kidins220 as a new binding partner of the BCR (Fiala et al., 2015). Kidins220 was first described as Kinase D-interacting substrate of 220 kDa in neuronal cells (Iglesias et al., 2000; Kong et al., 2001). As a scaffold protein, Kidins220 is implicated in multiple cellular processes like survival, proliferation and receptor signaling, among which are also the antigen receptors of T and B cells (Deswal et al., 2013; Fiala et al., 2015; Neubrand et al., 2012). The complete genetic deletion of Kidins220 is embryonically lethal (Cesca et al., 2012). Conditional mb1Cre-mediated B cell specific Kidins220 KO mice (B-KO) showed reduced BCR signaling, and almost complete loss of λLC B cells in the BM and periphery, with only mild effects on the κLC compartment (Fiala et al., 2015). Our new findings presented here indicate that Kidins220 is crucial for the generation of λLC B cells by supporting B cell progenitor survival and pre-BCR and BCR signaling, which allows for Igl locus opening, recombination, and protein expression.

We have previously discovered that the transmembrane protein Kidins220 binds to the BCR and regulates BCR signaling (Fiala et al., 2015). Deleting Kidins220 in B cells (B-KO mice) results in a severe reduction of λLC B cells despite normal generation of κLC B cells, generating thus a skewed antibody repertoire. Our data indicate that the absence of Kidins220 specifically prevents opening and/or transcription of the Igl locus. Remarkably, Kidins220-deficient B cells fail to open and recombine the Igl locus, even in genetic scenarios where the Igk genes cannot be rearranged (κ-KO). Our single-cell analysis of the frequencies of Igl-V-gene recombination has confirmed a clear preference for the recombination of Iglv1-gene in WT mice (Boudinot et al., 1994; Sanchez et al., 1996). This also holds true for B-KO mice. The current model proposes that this preference results from the cooperative function of the λ_1-3 and λ_2-4 enhancers, which surround the Igl-V-gene segments 3’ and 5’ of the λ1 and λ3 family and are bound by the same transcription factors (Collins and Watson, 2018; Haque et al., 2013). The distance of the λ_2-4 enhancer to the λ_1-3 enhancer might preclude that Igl gene recombination 5’ of the λ_2-4 enhancer profit from transcription factors and co-factors of the recombination machinery bound to the λ_1-3 enhancer. The rearrangement of the Iglv1 to Iglj1c1-gene segment eliminates the intervening sequence comprising the Iglj3c3-gene segment, resulting in the accumulation of λ1 LC B cells. Interestingly, we observed a relative increase in the usage of the genes of the λ3-family compared to the λ2-family in B-KO versus CTRL mice. This observation suggests that the recombination of the Igl-V-gene segments that are 5’ of the λ_2-4 enhancer is more depended on Kidins220 expression than the others. A possible explanation for this observation is that pre-BCR and BCR signaling are reduced in the absence of Kidins220 making the recombination of λ2-family V-genes unlikely. Instead, Iglv1 is recombined to Iglj3c3 more often in Kidins220-deficient mice. Together, our single-cell sequencing analysis supports that Kidins220 is dispensable for Igk, but essential for efficient Igl locus opening and gene recombination.

Reduced production of λLC B cells has been previously described in studies using mouse models with genetic deletion of signaling molecules downstream of the pre-BCR and BCR like BTK, SLP65, and PLCγ2 (Bai et al., 2007; Dingjan et al., 2001; Hayashi et al., 2004; Kersseboom et al., 2006; Middendorp et al., 2002; Stadhouders et al., 2014; Xu et al., 2007). In contrast, the combined deletion of some of these signaling components almost completely abolishes both Igl and Igk germline transcription, LC V-gene recombination, and protein expression (Kersseboom et al., 2006; Stadhouders et al., 2014; Xu et al., 2007). These data led to the interpretation that the generation of λLC B cells is more sensitive to defects in the signals transmitted by the pre-BCR and/or BCR (Stadhouders et al., 2014). Kidins220-deficiency has been previously described to dampen signaling by receptors in neurons, glial cells, adipocytes, T and B cells (Arévalo et al., 2004; Deswal et al., 2013; Fiala et al., 2015; Jaudon et al., 2020; Jaudon et al., 2021; López-Menéndez et al., 2009; Zhang et al., 2021). Indeed, BCR stimulation in a Kidins220 knockdown mature B cell line resulted in dampened activation of the RAS-ERK pathway due to an inefficient coupling of the BCR to the downstream Raf kinases B-Raf and Raf-1 (Fiala et al., 2015). Likewise, IgM-BCR-mediated stimulation of primary splenocytes from B-KO mice resulted in less phosphorylation of ERK and PLCγ2, as well as reduced calcium influx compared to CTRL cells; further highlighting the role of Kidins220 in BCR signaling (Fiala et al., 2015). Our data herein suggest that pre-BCR signaling is also reduced in the absence of Kidins220. Firstly, B-KO mice showed a reduction of the amount of MHCII⁺ and CD25⁺ cells as well as reduced CD25 surface expression on B cells in the BM. CD25 is upregulated upon pre-BCR signaling (Lee et al., 2015; Rolink et al., 1994), and its expression level is reduced in mice with genetic ablations of BTK, SLP65, or PLCγ2 (Kersseboom et al., 2003; Kersseboom et al., 2006; Middendorp et al., 2002; Stadhouders et al., 2014; Xu et al., 2007). Secondly, phosphorylation of the downstream MAPK family member ERK was reduced in pre- and immature B cell stages. Interestingly, in both of these stages active signaling takes place either ligand independent (pre-BCR) or ligand dependent (autoreactive BCR), respectively. It has been already described that (pre-) BCR signaling controls Rag expression via the MAPK/ERK pathway (Mandal et al., 2009; Mazari et al., 2007; Shaw et al., 1999). In the absence of Kidins220, the coupling of (pre-) BCR with the MAPK/ERK signaling pathway is defective resulting in insufficient upregulation of proteins needed for LC rearrangement (RAG, E47). It has been previously shown that interference with RAS-MEK signaling leads to upregulation of the negative regulator of E47, namely ID3, and a downregulation of Tcf3 (E47) transcripts and protein levels thus prohibiting its transcriptional function for LC rearrangement (Mandal et al., 2009). A similar scenario is conceivable in the context of Kidins220-deficiency. It is worth noting that rearrangement at the Igl locus demands higher levels of E2A activity (Beck et al., 2009). This further reinforces the notion that in the absence of Kidins220, the levels of RAG and E2A proteins are insufficient for rearranging the Igl locus while the Igk is rearranged normally. Thirdly, Kidins220-deficient B cells showed reduced ROS levels during BM development, especially in those stages where pre-BCR (small pre-B cells) and IgM-BCR signaling (immature B cells) is crucial. ROS are important second messengers (reviewed in Tsubata, 2020). In mature B cells, BCR activation induces ROS production to fully activate NF-κB signaling (Feng et al., 2019; Wheeler and Defranco, 2012). Considering the parallels between BCR and pre-BCR signaling, ROS might exert a similar role downstream of the pre-BCR. Indeed, previous reports have demonstrated that λLC B cell development but not κLC editing depends on NF-κB signals in line with our results (Derudder et al., 2009). In addition, ROS and MAPK/ERK pathways are manifold interconnected (reviewed in Corcoran and Cotter, 2013). ROS directly leads to the oxidization of certain amino acids in ERK leading to its activation and nuclear translocation (Galli et al., 2008). Furthermore, ROS are well-recognized as inactivators of phosphatases of the MAPK pathway (Kamata et al., 2005; Son et al., 2011) but also of phosphatases regulating BCR signaling (Reth, 2002; Singh et al., 2005) in non-hematopoietic cells. Thus, reduced generation of ROS in the absence of Kidins220 might lead to a higher activity of ERK-directed phosphatases, which eventually leads to the observed reduced phosphorylation of ERK in B-KO mice. Taken together, our findings support a mechanistic model in which Kidins220 mediates its effects by enhancing pre-BCR and BCR signaling. Still, we cannot formally rule out that Kidins220 might possess direct, signaling-dependent or -independent effects on the Igl locus opening.

Our data suggest that Kidins220 contributes to pre-B cell survival, which is necessary for LC gene recombination. In fact, a prolonged life-span in pre-B cells, induced by overexpression of anti-apoptotic BCL2, increases the amount of λLC⁺ B cells (Ait-Azzouzene et al., 2005; Derudder et al., 2009; Dingjan et al., 2001). BCL2 overexpression rescues the generation of λLC B cells in scenarios in which NF-κB signaling was abolished during B cell development (Derudder et al., 2009). A connection between (pre-) BCR signaling and survival is well recognized (Kraus et al., 2004; Meffre and Nussenzweig, 2002; Yasuda et al., 2008). However, there is limited data on the exact mechanism. In particular, pre-BCR signaling might lead to the activation of the NF-κB pathway, that in turn regulates the transcription of Pim2, a pro-survival protein in pre-B cells (Bednarski et al., 2012; Derudder et al., 2009; Siebenlist et al., 2005). Pre-BCR-mediated ERK activation might induce phosphorylation of the pro-apoptotic protein BIM and thereby interfere with its inhibitory interaction with BCL2, resulting in enhanced pre-B cell survival similar to reports on IgM-BCR signaling (Clark et al., 2014; Gold, 2008; O’Reilly et al., 2009). In addition, pre-BCR-mediated ERK signaling might induce Bcl2 transcription itself, thereby prolonging B cell survival during B cell development (Gold, 2008; Yasuda et al., 2008). Thus, the afore-discussed defects in coupling pre-BCR and/or BCR signaling to ERK activation in Kidins220-deficient B cells could lead to BCL2 levels that are insufficient to protect developing B cells from cell death. Indeed, ex vivo cultured B cell precursor from B-KO mice die faster upon IL-7 withdrawal (Fiala et al., 2015), and we also detected increased amounts of apoptotic cells during BM B cell development in these mice. However, overexpression of BCL2 did not fully rescue λLC-deficiency in B-KO mice, suggesting that prolong survival of B cell precursors is required, but not sufficient, to optimally generate λLC B cells in the absence of Kidins220 expression.

The κLC to λLC ratio is also affected by receptor editing. Receptor editing can lead to further recombination on either the same Igk allele, the second Igk allele or can proceed to the Igl locus (Luning Prak et al., 2011). The κ and λLCs differ in the physicochemical and structural properties of their CDR3 regions, and λLCs are proposed to be more effective in rescuing BCRs that show autoreactivity (Townsend et al., 2016; Wardemann et al., 2004). In line with previous studies, we show here that genetically forcing receptor editing using κ-deleting (κ-macroself) mice increased the production of B cells using the λLC in Kidins220 competent mice (Ait-Azzouzene et al., 2005; Beck et al., 2009). In the absence of Kidins220, strong autoreactive ligands efficiently induce the downregulation of surface κLC-BCRs indicating successful tolerance induction. However, the replacement of the autoreactive κLC by an innocuous λLC was severely impaired in the absence of Kidins220. These data underline the importance of Kidins220 for Igl gene recombination, even under the high selective pressure imposed by the κ-macroself mice. Indeed, overexpression of BCL2 did not profoundly enhance λLC expression by B-KO cells in the κ-macroself recipients, highlighting again that increasing survival is not sufficient to optimally obtain λLC B cells in the absence of Kidins220 expression. The data obtained in the κ-macroself mice are in line with our single-cell repertoire analysis showing that we did not find any signs of potentially autoreactive BCRs in B-KO mice. Since Kidins220-deficient B cells do not open the Igl locus efficiently, secondary rearrangement at the Igk locus should be increased. Indeed, we observed a slight increase in the Igkj5-gene usage in B-KO mice compared to CTRLs. Igkj5 is associated with several rounds of secondary rearrangement and often represents the last rearrangement before silencing of the Igk locus by recombining sequence recombination (Prak et al., 1994; Retter and Nemazee, 1998).

To conclude, our study demonstrates that Kidins220 supports pre-B cell survival and promotes pre-BCR and BCR signaling via ROS and ERK to allow Igl locus opening and λLC expression during both homeostatic B cell development and receptor editing. The heightened sensitivity of the Igl locus, compared to the Igk locus, to reductions in expression and activity of recombination machinery proteins regulated by pre-BCR and BCR signals (Bai et al., 2007; Beck et al., 2009; Johnson et al., 2008; Novak et al., 2010; Pathak et al., 2008; Vela et al., 2008; Verkoczy et al., 2005), explains why the absence of Kidins220 specifically impacts Igl gene rearrangement. This study adds thus to our understanding of the underlying mechanism regulating the differential expression of the κ and λLCs in B cells and the generation of a self-tolerant repertoire.

All data generated or analysed during this study are included in the manuscript and supporting files.

1. 1. Ait-Azzouzene D
   2. Verkoczy L
   3. Peters J
   4. Gavin A
   5. Skog P
   6. Vela JL
   7. Nemazee D

   (2005) An immunoglobulin C kappa-reactive single chain antibody fusion protein induces tolerance through receptor editing in a normal polyclonal immune system

   The Journal of Experimental Medicine 201:817–828.

   https://doi.org/10.1084/jem.20041854

   • PubMed
   • Google Scholar
2. 1. Aoki-Ota M
   2. Torkamani A
   3. Ota T
   4. Schork N
   5. Nemazee D

   (2012) Skewed primary Igκ repertoire and V-J joining in C57BL/6 mice: implications for recombination accessibility and receptor editing

   Journal of Immunology 188:2305–2315.

   https://doi.org/10.4049/jimmunol.1103484

   • PubMed
   • Google Scholar
3. 1. Arévalo JC
   2. Yano H
   3. Teng KK
   4. Chao MV

   (2004) A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein

   The EMBO Journal 23:2358–2368.

   https://doi.org/10.1038/sj.emboj.7600253

   • PubMed
   • Google Scholar
4. 1. Bae YS
   2. Oh H
   3. Rhee SG
   4. Yoo YD

   (2011) Regulation of reactive oxygen species generation in cell signaling

   Molecules and Cells 32:491–509.

   https://doi.org/10.1007/s10059-011-0276-3

   • PubMed
   • Google Scholar
5. 1. Bai L
   2. Chen Y
   3. He Y
   4. Dai X
   5. Lin X
   6. Wen R
   7. Wang D

   (2007) Phospholipase Cgamma2 contributes to light-chain gene activation and receptor editing

   Molecular and Cellular Biology 27:5957–5967.

   https://doi.org/10.1128/MCB.02273-06

   • PubMed
   • Google Scholar
6. 1. Banerjee A
   2. Grumont R
   3. Gugasyan R
   4. White C
   5. Strasser A
   6. Gerondakis S

   (2008) NF-kappaB1 and c-Rel cooperate to promote the survival of TLR4-activated B cells by neutralizing Bim via distinct mechanisms

   Blood 112:5063–5073.

   https://doi.org/10.1182/blood-2007-10-120832

   • PubMed
   • Google Scholar
7. 1. Beck K
   2. Peak MM
   3. Ota T
   4. Nemazee D
   5. Murre C

   (2009) Distinct roles for E12 and E47 in B cell specification and the sequential rearrangement of immunoglobulin light chain loci

   The Journal of Experimental Medicine 206:2271–2284.

   https://doi.org/10.1084/jem.20090756

   • PubMed
   • Google Scholar
8. 1. Bednarski JJ
   2. Nickless A
   3. Bhattacharya D
   4. Amin RH
   5. Schlissel MS
   6. Sleckman BP

   (2012) RAG-induced DNA double-strand breaks signal through Pim2 to promote pre-B cell survival and limit proliferation

   The Journal of Experimental Medicine 209:11–17.

   https://doi.org/10.1084/jem.20112078

   • PubMed
   • Google Scholar
9. 1. Boudinot P
   2. Drapier AM
   3. Cazenave PA
   4. Sanchez P

   (1994) Conserved distribution of lambda subtypes from rearranged gene segments to immunoglobulin synthesis in the mouse B cell repertoire

   European Journal of Immunology 24:2013–2017.

   https://doi.org/10.1002/eji.1830240912

   • PubMed
   • Google Scholar
10. 1. Cesca F
    2. Yabe A
    3. Spencer-Dene B
    4. Scholz-Starke J
    5. Medrihan L
    6. Maden CH
    7. Gerhardt H
    8. Orriss IR
    9. Baldelli P
    10. Al-Qatari M
    11. Koltzenburg M
    12. Adams RH
    13. Benfenati F
    14. Schiavo G

    (2012) Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascular and nervous systems

    Cell Death and Differentiation 19:194–208.

    https://doi.org/10.1038/cdd.2011.141

    • PubMed
    • Google Scholar
11. 1. Clark MR
    2. Mandal M
    3. Ochiai K
    4. Singh H

    (2014) Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling

    Nature Reviews. Immunology 14:69–80.

    https://doi.org/10.1038/nri3570

    • PubMed
    • Google Scholar
12. 1. Collins AM
    2. Watson CT

    (2018) Immunoglobulin light chain gene rearrangements, receptor editing and the development of a self-tolerant antibody repertoire

    Frontiers in Immunology 9:2249.

    https://doi.org/10.3389/fimmu.2018.02249

    • PubMed
    • Google Scholar
13. 1. Corcoran A
    2. Cotter TG

    (2013) Redox regulation of protein kinases

    The FEBS Journal 280:1944–1965.

    https://doi.org/10.1111/febs.12224

    • PubMed
    • Google Scholar
14. 1. Derudder E
    2. Cadera EJ
    3. Vahl JC
    4. Wang J
    5. Fox CJ
    6. Zha S
    7. van Loo G
    8. Pasparakis M
    9. Schlissel MS
    10. Schmidt-Supprian M
    11. Rajewsky K

    (2009) Development of immunoglobulin lambda-chain-positive B cells, but not editing of immunoglobulin kappa-chain, depends on NF-kappaB signals

    Nature Immunology 10:647–654.

    https://doi.org/10.1038/ni.1732

    • PubMed
    • Google Scholar
15. 1. Derudder E
    2. Herzog S
    3. Labi V
    4. Yasuda T
    5. Köchert K
    6. Janz M
    7. Villunger A
    8. Schmidt-Supprian M
    9. Rajewsky K

    (2016) Canonical NF-κB signaling is uniquely required for the long-term persistence of functional mature B cells

    PNAS 113:5065–5070.

    https://doi.org/10.1073/pnas.1604529113

    • PubMed
    • Google Scholar
16. 1. Deswal S
    2. Meyer A
    3. Fiala GJ
    4. Eisenhardt AE
    5. Schmitt LC
    6. Salek M
    7. Brummer T
    8. Acuto O
    9. Schamel WWA

    (2013) Kidins220/ARMS associates with B-Raf and the TCR, promoting sustained Erk signaling in T cells

    Journal of Immunology 190:1927–1935.

    https://doi.org/10.4049/jimmunol.1200653

    • PubMed
    • Google Scholar
17. 1. Dingjan GM
    2. Middendorp S
    3. Dahlenborg K
    4. Maas A
    5. Grosveld F
    6. Hendriks RW

    (2001) Bruton’s tyrosine kinase regulates the activation of gene rearrangements at the lambda light chain locus in precursor B cells in the mouse

    The Journal of Experimental Medicine 193:1169–1178.

    https://doi.org/10.1084/jem.193.10.1169

    • PubMed
    • Google Scholar
18. 1. Duffy AM
    2. Schaner MJ
    3. Wu SH
    4. Staniszewski A
    5. Kumar A
    6. Arévalo JC
    7. Arancio O
    8. Chao MV
    9. Scharfman HE

    (2011) A selective role for ARMS/Kidins220 scaffold protein in spatial memory and trophic support of entorhinal and frontal cortical neurons

    Experimental Neurology 229:409–420.

    https://doi.org/10.1016/j.expneurol.2011.03.008

    • PubMed
    • Google Scholar
19. 1. Engel H
    2. Rolink A
    3. Weiss S

    (1999) B cells are programmed to activate kappa and lambda for rearrangement at consecutive developmental stages

    European Journal of Immunology 29:2167–2176.

    https://doi.org/10.1002/(SICI)1521-4141(199907)29:07<2167::AID-IMMU2167>3.0.CO;2-H

    • PubMed
    • Google Scholar
20. 1. Engel H
    2. Rühl H
    3. Benham CJ
    4. Bode J
    5. Weiss S

    (2001) Germ-line transcripts of the immunoglobulin lambda J-C clusters in the mouse: characterization of the initiation sites and regulatory elements

    Molecular Immunology 38:289–302.

    https://doi.org/10.1016/s0161-5890(01)00056-6

    • PubMed
    • Google Scholar
21. 1. Feng YY
    2. Tang M
    3. Suzuki M
    4. Gunasekara C
    5. Anbe Y
    6. Hiraoka Y
    7. Liu J
    8. Grasberger H
    9. Ohkita M
    10. Matsumura Y
    11. Wang JY
    12. Tsubata T

    (2019) Essential role of NADPH oxidase-dependent production of reactive oxygen species in maintenance of sustained B cell receptor signaling and B cell proliferation

    Journal of Immunology 202:2546–2557.

    https://doi.org/10.4049/jimmunol.1800443

    • PubMed
    • Google Scholar
22. 1. Fiala GJ
    2. Janowska I
    3. Prutek F
    4. Hobeika E
    5. Satapathy A
    6. Sprenger A
    7. Plum T
    8. Seidl M
    9. Dengjel J
    10. Reth M
    11. Cesca F
    12. Brummer T
    13. Minguet S
    14. Schamel WWA

    (2015) Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation

    The Journal of Experimental Medicine 212:1693–1708.

    https://doi.org/10.1084/jem.20141271

    • PubMed
    • Google Scholar
23. 1. Flemming A
    2. Brummer T
    3. Reth M
    4. Jumaa H

    (2003) The adaptor protein SLP-65 acts as a tumor suppressor that limits pre-B cell expansion

    Nature Immunology 4:38–43.

    https://doi.org/10.1038/ni862

    • PubMed
    • Google Scholar
24. 1. Galli S
    2. Antico Arciuch VG
    3. Poderoso C
    4. Converso DP
    5. Zhou Q
    6. Bal de Kier Joffé E
    7. Cadenas E
    8. Boczkowski J
    9. Carreras MC
    10. Poderoso JJ

    (2008) Tumor cell phenotype is sustained by selective MAPK oxidation in mitochondria

    PLOS ONE 3:e2379.

    https://doi.org/10.1371/journal.pone.0002379

    • PubMed
    • Google Scholar
25. 1. Gerdes T
    2. Wabl M

    (2002) Physical map of the mouse lambda light chain and related loci

    Immunogenetics 54:62–65.

    https://doi.org/10.1007/s00251-002-0435-y

    • PubMed
    • Google Scholar
26. 1. Gold MR

    (2008) B cell development: important work for ERK

    Immunity 28:488–490.

    https://doi.org/10.1016/j.immuni.2008.03.008

    • PubMed
    • Google Scholar
27. 1. Goodnow CC

    (1996) Balancing immunity and tolerance: deleting and tuning lymphocyte repertoires

    PNAS 93:2264–2271.

    https://doi.org/10.1073/pnas.93.6.2264

    • PubMed
    • Google Scholar
28. 1. Haque SFY
    2. Bevington SL
    3. Boyes J

    (2013) The Eλ(3-1) enhancer is essential for V(D)J recombination of the murine immunoglobulin lambda light chain locus

    Biochemical and Biophysical Research Communications 441:482–487.

    https://doi.org/10.1016/j.bbrc.2013.10.087

    • PubMed
    • Google Scholar
29. 1. Hashimoto A
    2. Takeda K
    3. Inaba M
    4. Sekimata M
    5. Kaisho T
    6. Ikehara S
    7. Homma Y
    8. Akira S
    9. Kurosaki T

    (2000) Cutting edge: essential role of phospholipase C-gamma 2 in B cell development and function

    Journal of Immunology 165:1738–1742.

    https://doi.org/10.4049/jimmunol.165.4.1738

    • PubMed
    • Google Scholar
30. 1. Hayashi K
    2. Nojima T
    3. Goitsuka R
    4. Kitamura D

    (2004) Impaired receptor editing in the primary B cell repertoire of BASH-deficient mice

    Journal of Immunology 173:5980–5988.

    https://doi.org/10.4049/jimmunol.173.10.5980

    • PubMed
    • Google Scholar
31. 1. Herzog S
    2. Reth M
    3. Jumaa H

    (2009) Regulation of B-cell proliferation and differentiation by pre-B-cell receptor signalling

    Nature Reviews. Immunology 9:195–205.

    https://doi.org/10.1038/nri2491

    • PubMed
    • Google Scholar
32. 1. Hsu LY
    2. Lauring J
    3. Liang HE
    4. Greenbaum S
    5. Cado D
    6. Zhuang Y
    7. Schlissel MS

    (2003) A conserved transcriptional enhancer regulates RAG gene expression in developing B cells

    Immunity 19:105–117.

    https://doi.org/10.1016/s1074-7613(03)00181-x

    • PubMed
    • Google Scholar
33. 1. Iglesias T
    2. Cabrera-Poch N
    3. Mitchell MP
    4. Naven TJ
    5. Rozengurt E
    6. Schiavo G

    (2000) Identification and cloning of Kidins220, a novel neuronal substrate of protein kinase D

    The Journal of Biological Chemistry 275:40048–40056.

    https://doi.org/10.1074/jbc.M005261200

    • PubMed
    • Google Scholar
34. 1. Inlay MA
    2. Tian H
    3. Lin T
    4. Xu Y

    (2004) Important roles for E protein binding sites within the immunoglobulin kappa chain intronic enhancer in activating Vkappa Jkappa rearrangement

    The Journal of Experimental Medicine 200:1205–1211.

    https://doi.org/10.1084/jem.20041135

    • PubMed
    • Google Scholar
35. 1. Jaudon F
    2. Chiacchiaretta M
    3. Albini M
    4. Ferroni S
    5. Benfenati F
    6. Cesca F

    (2020) Kidins220/ARMS controls astrocyte calcium signaling and neuron-astrocyte communication

    Cell Death and Differentiation 27:1505–1519.

    https://doi.org/10.1038/s41418-019-0431-5

    • PubMed
    • Google Scholar
36. 1. Jaudon F
    2. Albini M
    3. Ferroni S
    4. Benfenati F
    5. Cesca F

    (2021) A developmental stage- and Kidins220-dependent switch in astrocyte responsiveness to brain-derived neurotrophic factor

    Journal of Cell Science 134:jcs258419.

    https://doi.org/10.1242/jcs.258419

    • PubMed
    • Google Scholar
37. 1. Johnson K
    2. Hashimshony T
    3. Sawai CM
    4. Pongubala JMR
    5. Skok JA
    6. Aifantis I
    7. Singh H

    (2008) Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling

    Immunity 28:335–345.

    https://doi.org/10.1016/j.immuni.2007.12.019

    • PubMed
    • Google Scholar
38. 1. Johnson K
    2. Chaumeil J
    3. Micsinai M
    4. Wang JMH
    5. Ramsey LB
    6. Baracho GV
    7. Rickert RC
    8. Strino F
    9. Kluger Y
    10. Farrar MA
    11. Skok JA

    (2012) IL-7 functionally segregates the pro-B cell stage by regulating transcription of recombination mediators across cell cycle

    Journal of Immunology 188:6084–6092.

    https://doi.org/10.4049/jimmunol.1200368

    • PubMed
    • Google Scholar
39. 1. Kamata H
    2. Honda SI
    3. Maeda S
    4. Chang L
    5. Hirata H
    6. Karin M

    (2005) Reactive oxygen species promote TNFalpha-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases

    Cell 120:649–661.

    https://doi.org/10.1016/j.cell.2004.12.041

    • PubMed
    • Google Scholar
40. 1. Karasuyama H
    2. Kudo A
    3. Melchers F

    (1990) The proteins encoded by the VpreB and lambda 5 pre-B cell-specific genes can associate with each other and with mu heavy chain

    The Journal of Experimental Medicine 172:969–972.

    https://doi.org/10.1084/jem.172.3.969

    • PubMed
    • Google Scholar
41. 1. Kenter AL
    2. Watson CT
    3. Spille JH

    (2021) Igh locus polymorphism may dictate topological chromatin conformation and V gene usage in the Ig repertoire

    Frontiers in Immunology 12:682589.

    https://doi.org/10.3389/fimmu.2021.682589

    • PubMed
    • Google Scholar
42. 1. Kersseboom R
    2. Middendorp S
    3. Dingjan GM
    4. Dahlenborg K
    5. Reth M
    6. Jumaa H
    7. Hendriks RW

    (2003) Bruton’s tyrosine kinase cooperates with the B cell linker protein SLP-65 as a tumor suppressor in Pre-B cells

    The Journal of Experimental Medicine 198:91–98.

    https://doi.org/10.1084/jem.20030615

    • PubMed
    • Google Scholar
43. 1. Kersseboom R
    2. Ta VBT
    3. Zijlstra AJE
    4. Middendorp S
    5. Jumaa H
    6. van Loo PF
    7. Hendriks RW

    (2006) Bruton’s tyrosine kinase and SLP-65 regulate pre-B cell differentiation and the induction of Ig light chain gene rearrangement

    Journal of Immunology 176:4543–4552.

    https://doi.org/10.4049/jimmunol.176.8.4543

    • PubMed
    • Google Scholar
44. 1. Kong H
    2. Boulter J
    3. Weber JL
    4. Lai C
    5. Chao MV

    (2001) An evolutionarily conserved transmembrane protein that is a novel downstream target of neurotrophin and ephrin receptors

    The Journal of Neuroscience 21:176–185.

    https://doi.org/10.1523/JNEUROSCI.21-01-00176.2001

    • PubMed
    • Google Scholar
45. 1. Kraus M
    2. Alimzhanov MB
    3. Rajewsky N
    4. Rajewsky K

    (2004) Survival of resting mature B lymphocytes depends on BCR signaling via the Igalpha/beta heterodimer

    Cell 117:787–800.

    https://doi.org/10.1016/j.cell.2004.05.014

    • PubMed
    • Google Scholar
46. 1. Lang J
    2. Arnold B
    3. Hammerling G
    4. Harris AW
    5. Korsmeyer S
    6. Russell D
    7. Strasser A
    8. Nemazee D

    (1997) Enforced Bcl-2 expression inhibits antigen-mediated clonal elimination of peripheral B cells in an antigen dose-dependent manner and promotes receptor editing in autoreactive, immature B cells

    The Journal of Experimental Medicine 186:1513–1522.

    https://doi.org/10.1084/jem.186.9.1513

    • PubMed
    • Google Scholar
47. 1. Lazorchak AS
    2. Schlissel MS
    3. Zhuang Y

    (2006) E2A and IRF-4/Pip promote chromatin modification and transcription of the immunoglobulin kappa locus in pre-B cells

    Molecular and Cellular Biology 26:810–821.

    https://doi.org/10.1128/MCB.26.3.810-821.2006

    • PubMed
    • Google Scholar
48. 1. Lee JW
    2. Chen Z
    3. Geng H
    4. Xiao G
    5. Park E
    6. Parekh S
    7. Kornblau SM
    8. Melnick A
    9. Abbas A
    10. Paietta E
    11. Muschen M

    (2015) CD25 (IL2RA) orchestrates negative feedback control and stabilizes oncogenic signaling strength in acute lymphoblastic leukemia

    Blood 126:1434.

    https://doi.org/10.1182/blood.V126.23.1434.1434

    • Google Scholar
49. 1. López-Menéndez C
    2. Gascón S
    3. Sobrado M
    4. Vidaurre OG
    5. Higuero AM
    6. Rodríguez-Peña A
    7. Iglesias T
    8. Díaz-Guerra M

    (2009) Kidins220/ARMS downregulation by excitotoxic activation of NMDARs reveals its involvement in neuronal survival and death pathways

    Journal of Cell Science 122:3554–3565.

    https://doi.org/10.1242/jcs.056473

    • PubMed
    • Google Scholar
50. 1. Lu R
    2. Medina KL
    3. Lancki DW
    4. Singh H

    (2003) IRF-4,8 orchestrate the pre-B-to-B transition in lymphocyte development

    Genes & Development 17:1703–1708.

    https://doi.org/10.1101/gad.1104803

    • PubMed
    • Google Scholar
51. 1. Luning Prak ET
    2. Monestier M
    3. Eisenberg RA

    (2011) B cell receptor editing in tolerance and autoimmunity

    Annals of the New York Academy of Sciences 1217:96–121.

    https://doi.org/10.1111/j.1749-6632.2010.05877.x

    • PubMed
    • Google Scholar
52. 1. Ma S
    2. Turetsky A
    3. Trinh L
    4. Lu R

    (2006) IFN regulatory factor 4 and 8 promote Ig light chain kappa locus activation in pre-B cell development

    Journal of Immunology 177:7898–7904.

    https://doi.org/10.4049/jimmunol.177.11.7898

    • PubMed
    • Google Scholar
53. 1. Ma S
    2. Pathak S
    3. Trinh L
    4. Lu R

    (2008) Interferon regulatory factors 4 and 8 induce the expression of Ikaros and Aiolos to down-regulate pre-B-cell receptor and promote cell-cycle withdrawal in pre-B-cell development

    Blood 111:1396–1403.

    https://doi.org/10.1182/blood-2007-08-110106

    • PubMed
    • Google Scholar
54. 1. Ma S
    2. Pathak S
    3. Mandal M
    4. Trinh L
    5. Clark MR
    6. Lu R

    (2010) Ikaros and Aiolos inhibit pre-B-cell proliferation by directly suppressing c-Myc expression

    Molecular and Cellular Biology 30:4149–4158.

    https://doi.org/10.1128/MCB.00224-10

    • PubMed
    • Google Scholar
55. 1. Mandal M
    2. Powers SE
    3. Ochiai K
    4. Georgopoulos K
    5. Kee BL
    6. Singh H
    7. Clark MR

    (2009) Ras orchestrates exit from the cell cycle and light-chain recombination during early B cell development

    Nature Immunology 10:1110–1117.

    https://doi.org/10.1038/ni.1785

    • PubMed
    • Google Scholar
56. 1. Maranhão AQ
    2. Costa MBW
    3. Guedes L
    4. Moraes-Vieira PM
    5. Raiol T
    6. Brigido MM

    (2013) A mouse variable gene fragment binds to DNA independently of the BCR context: A possible role for immature B-cell repertoire establishment

    PLOS ONE 8:e72625.

    https://doi.org/10.1371/journal.pone.0072625

    • PubMed
    • Google Scholar
57. 1. Matthias P
    2. Rolink AG

    (2005) Transcriptional networks in developing and mature B cells

    Nature Reviews. Immunology 5:497–508.

    https://doi.org/10.1038/nri1633

    • PubMed
    • Google Scholar
58. 1. Mazari L
    2. Ouarzane M
    3. Zouali M

    (2007) Subversion of B lymphocyte tolerance by hydralazine, a potential mechanism for drug-induced lupus

    PNAS 104:6317–6322.

    https://doi.org/10.1073/pnas.0610434104

    • PubMed
    • Google Scholar
59. 1. McGuire KL
    2. Vitetta ES

    (1981) kappa/lambda Shifts do not occur during maturation of murine B cells

    Journal of Immunology 127:1670–1673.

    https://doi.org/10.4049/jimmunol.127.4.1670

    • PubMed
    • Google Scholar
60. 1. Meffre E
    2. Nussenzweig MC

    (2002) Deletion of immunoglobulin beta in developing B cells leads to cell death

    PNAS 99:11334–11339.

    https://doi.org/10.1073/pnas.172369999

    • PubMed
    • Google Scholar
61. 1. Middendorp S
    2. Dingjan GM
    3. Hendriks RW

    (2002) Impaired precursor B cell differentiation in Bruton’s tyrosine kinase-deficient mice

    Journal of Immunology 168:2695–2703.

    https://doi.org/10.4049/jimmunol.168.6.2695

    • PubMed
    • Google Scholar
62. 1. Miho E
    2. Roškar R
    3. Greiff V
    4. Reddy ST

    (2019) Large-scale network analysis reveals the sequence space architecture of antibody repertoires

    Nature Communications 10:1321.

    https://doi.org/10.1038/s41467-019-09278-8

    • PubMed
    • Google Scholar
63. 1. Nemazee D

    (2006) Receptor editing in lymphocyte development and central tolerance

    Nature Reviews. Immunology 6:728–740.

    https://doi.org/10.1038/nri1939

    • PubMed
    • Google Scholar
64. 1. Neubrand VE
    2. Cesca F
    3. Benfenati F
    4. Schiavo G

    (2012) Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways

    Journal of Cell Science 125:1845–1854.

    https://doi.org/10.1242/jcs.102764

    • PubMed
    • Google Scholar
65. 1. Novak R
    2. Jacob E
    3. Haimovich J
    4. Avni O
    5. Melamed D

    (2010) The MAPK/ERK and PI3K pathways additively coordinate the transcription of recombination-activating genes in B lineage cells

    Journal of Immunology 185:3239–3247.

    https://doi.org/10.4049/jimmunol.1001430

    • PubMed
    • Google Scholar
66. 1. Ochiai K
    2. Maienschein-Cline M
    3. Mandal M
    4. Triggs JR
    5. Bertolino E
    6. Sciammas R
    7. Dinner AR
    8. Clark MR
    9. Singh H

    (2012) A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation

    Nature Immunology 13:300–307.

    https://doi.org/10.1038/ni.2210

    • PubMed
    • Google Scholar
67. 1. Oettinger MA
    2. Schatz DG
    3. Gorka C
    4. Baltimore D

    (1990) RAG-1 and RAG-2, adjacent genes that synergistically activate V(D)J recombination

    Science 248:1517–1523.

    https://doi.org/10.1126/science.2360047

    • PubMed
    • Google Scholar
68. 1. Ogilvy S
    2. Metcalf D
    3. Print CG
    4. Bath ML
    5. Harris AW
    6. Adams JM

    (1999) Constitutive Bcl-2 expression throughout the hematopoietic compartment affects multiple lineages and enhances progenitor cell survival

    PNAS 96:14943–14948.

    https://doi.org/10.1073/pnas.96.26.14943

    • PubMed
    • Google Scholar
69. 1. O’Reilly LA
    2. Kruse EA
    3. Puthalakath H
    4. Kelly PN
    5. Kaufmann T
    6. Huang DCS
    7. Strasser A

    (2009) MEK/ERK-mediated phosphorylation of Bim is required to ensure survival of T and B lymphocytes during mitogenic stimulation

    Journal of Immunology 183:261–269.

    https://doi.org/10.4049/jimmunol.0803853

    • PubMed
    • Google Scholar
70. 1. Pathak S
    2. Ma S
    3. Trinh L
    4. Lu R

    (2008) A role for interferon regulatory factor 4 in receptor editing

    Molecular and Cellular Biology 28:2815–2824.

    https://doi.org/10.1128/MCB.01946-07

    • PubMed
    • Google Scholar
71. 1. Pillai S
    2. Cariappa A

    (2009) The follicular versus marginal zone B lymphocyte cell fate decision

    Nature Reviews. Immunology 9:767–777.

    https://doi.org/10.1038/nri2656

    • PubMed
    • Google Scholar
72. 1. Prak EL
    2. Trounstine M
    3. Huszar D
    4. Weigert M

    (1994) Light chain editing in kappa-deficient animals: a potential mechanism of B cell tolerance

    The Journal of Experimental Medicine 180:1805–1815.

    https://doi.org/10.1084/jem.180.5.1805

    • PubMed
    • Google Scholar
73. 1. Quong MW
    2. Martensson A
    3. Langerak AW
    4. Rivera RR
    5. Nemazee D
    6. Murre C

    (2004) Receptor editing and marginal zone B cell development are regulated by the helix-loop-helix protein, E2A

    The Journal of Experimental Medicine 199:1101–1112.

    https://doi.org/10.1084/jem.20031180

    • PubMed
    • Google Scholar
74. 1. Reilly EB
    2. Blomberg B
    3. Imanishi-Kari T
    4. Tonegawa S
    5. Eisen HN

    (1984) Restricted association of V and J-C gene segments for mouse lambda chains

    PNAS 81:2484–2488.

    https://doi.org/10.1073/pnas.81.8.2484

    • PubMed
    • Google Scholar
75. 1. Reth MG
    2. Ammirati P
    3. Jackson S
    4. Alt FW

    (1985) Regulated progression of a cultured pre-B-cell line to the B-cell stage

    Nature 317:353–355.

    https://doi.org/10.1038/317353a0

    • Google Scholar
76. 1. Reth M

    (2002) Hydrogen peroxide as second messenger in lymphocyte activation

    Nature Immunology 3:1129–1134.

    https://doi.org/10.1038/ni1202-1129

    • PubMed
    • Google Scholar
77. 1. Reth M
    2. Nielsen P

    (2014) Signaling circuits in early B-cell development

    Advances in Immunology 122:129–175.

    https://doi.org/10.1016/B978-0-12-800267-4.00004-3

    • Google Scholar
78. 1. Retter MW
    2. Nemazee D

    (1998) Receptor editing occurs frequently during normal B cell development

    The Journal of Experimental Medicine 188:1231–1238.

    https://doi.org/10.1084/jem.188.7.1231

    • Google Scholar
79. 1. Rolink A
    2. Streb M
    3. Melchers F

    (1991) The kappa/lambda ratio in surface immunoglobulin molecules on B lymphocytes differentiating from DHJH-rearranged murine pre-B cell clones in vitro

    European Journal of Immunology 21:2895–2898.

    https://doi.org/10.1002/eji.1830211137

    • PubMed
    • Google Scholar
80. 1. Rolink A
    2. Grawunder U
    3. Winkler TH
    4. Karasuyama H
    5. Melchers F

    (1994) IL-2 receptor α chain (CD25JAC) expression defines a crucial stage in pre-B cell development

    International Immunology 6:1257–1264.

    https://doi.org/10.1093/intimm/6.8.1257

    • Google Scholar
81. 1. Rolink AG
    2. ten Boekel E
    3. Yamagami T
    4. Ceredig R
    5. Andersson J
    6. Melchers F

    (1999) B cell development in the mouse from early progenitors to mature B cells

    Immunology Letters 68:89–93.

    https://doi.org/10.1016/s0165-2478(99)00035-8

    • PubMed
    • Google Scholar
82. 1. Sanchez P
    2. Nadel B
    3. Cazenave PA

    (1991) V lambda-J lambda rearrangements are restricted within a V-J-C recombination unit in the mouse

    European Journal of Immunology 21:907–911.

    https://doi.org/10.1002/eji.1830210408

    • PubMed
    • Google Scholar
83. 1. Sanchez P
    2. Rueff-Juy D
    3. Boudinot P
    4. Hachemi-Rachedi S
    5. Cazenave PA

    (1996) The lambda B cell repertoire of kappa-deficient mice

    International Reviews of Immunology 13:357–368.

    https://doi.org/10.3109/08830189609061758

    • PubMed
    • Google Scholar
84. 1. Schatz DG
    2. Oettinger MA
    3. Baltimore D

    (1989) The V(D)J recombination activating gene, RAG-1

    Cell 59:1035–1048.

    https://doi.org/10.1016/0092-8674(89)90760-5

    • PubMed
    • Google Scholar
85. 1. Schlissel MS
    2. Baltimore D

    (1989) Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription

    Cell 58:1001–1007.

    https://doi.org/10.1016/0092-8674(89)90951-3

    • PubMed
    • Google Scholar
86. 1. Shaw AC
    2. Swat W
    3. Davidson L
    4. Alt FW

    (1999) Induction of Ig light chain gene rearrangement in heavy chain-deficient B cells by activated Ras

    PNAS 96:2239–2243.

    https://doi.org/10.1073/pnas.96.5.2239

    • Google Scholar
87. 1. Siebenlist U
    2. Brown K
    3. Claudio E

    (2005) Control of lymphocyte development by nuclear factor-kappaB

    Nature Reviews. Immunology 5:435–445.

    https://doi.org/10.1038/nri1629

    • PubMed
    • Google Scholar
88. 1. Singh DK
    2. Kumar D
    3. Siddiqui Z
    4. Basu SK
    5. Kumar V
    6. Rao KVS

    (2005) The strength of peceptor signaling is centrally controlled through a cooperative loop between Ca2+ and an oxidant signal

    Cell 121:281–293.

    https://doi.org/10.1016/j.cell.2005.02.036

    • Google Scholar
89. 1. Smakaj E
    2. Babrak L
    3. Ohlin M
    4. Shugay M
    5. Briney B
    6. Tosoni D
    7. Galli C
    8. Grobelsek V
    9. D’Angelo I
    10. Olson B
    11. Reddy S
    12. Greiff V
    13. Trück J
    14. Marquez S
    15. Lees W
    16. Miho E
    17. Birols I

    (2020) Benchmarking immunoinformatic tools for the analysis of antibody repertoire sequences

    Bioinformatics 36:1731–1739.

    https://doi.org/10.1093/bioinformatics/btz845

    • Google Scholar
90. 1. Son Y
    2. Cheong YK
    3. Kim NH
    4. Chung HT
    5. Kang DG
    6. Pae HO

    (2011) Mitogen-activated protein kinases and reactive oxygen species: how can ROS activate MAPK pathways?

    Journal of Signal Transduction 2011:1–6.

    https://doi.org/10.1155/2011/792639

    • Google Scholar
91. 1. Stadhouders R
    2. de Bruijn MJW
    3. Rother MB
    4. Yuvaraj S
    5. Ribeiro de Almeida C
    6. Kolovos P
    7. Van Zelm MC
    8. van Ijcken W
    9. Grosveld F
    10. Soler E
    11. Hendriks RW

    (2014) Pre-B cell receptor signaling induces immunoglobulin κ locus accessibility by functional redistribution of enhancer-mediated chromatin interactions

    PLOS Biology 12:e1001791.

    https://doi.org/10.1371/journal.pbio.1001791

    • PubMed
    • Google Scholar
92. 1. Stein M
    2. Dütting S
    3. Mougiakakos D
    4. Bösl M
    5. Fritsch K
    6. Reimer D
    7. Urbanczyk S
    8. Steinmetz T
    9. Schuh W
    10. Bozec A
    11. Winkler TH
    12. Jäck HM
    13. Mielenz D

    (2017) A defined metabolic state in pre B cells governs B-cell development and is counterbalanced by Swiprosin-2/EFhd1

    Cell Death & Differentiation 24:1239–1252.

    https://doi.org/10.1038/cdd.2017.52

    • Google Scholar
93. 1. Sun Y
    2. Wei Z
    3. Li N
    4. Zhao Y

    (2013) A comparative overview of immunoglobulin genes and the generation of their diversity in tetrapods

    Developmental & Comparative Immunology 39:103–109.

    https://doi.org/10.1016/j.dci.2012.02.008

    • Google Scholar
94. 1. Takeda S
    2. Zou YR
    3. Bluethmann H
    4. Kitamura D
    5. Muller U
    6. Rajewsky K

    (1993) Deletion of the immunoglobulin kappa chain intron enhancer abolishes kappa chain gene rearrangement in cis but not lambda chain gene rearrangement in trans

    The EMBO Journal 12:2329–2336.

    https://doi.org/10.1002/j.1460-2075.1993.tb05887.x

    • PubMed
    • Google Scholar
95. 1. Townsend CL
    2. Laffy JMJ
    3. Wu YCB
    4. Silva O’Hare J
    5. Martin V
    6. Kipling D
    7. Fraternali F
    8. Dunn-Walters DK

    (2016) Significant differences in physicochemical properties of human immunoglobulin kappa and lambda CDR3 regions

    Frontiers in Immunology 7:00388.

    https://doi.org/10.3389/fimmu.2016.00388

    • Google Scholar
96. 1. Trancoso I
    2. Bonnet M
    3. Gardner R
    4. Carneiro J
    5. Barreto VM
    6. Demengeot J
    7. Sarmento LM

    (2013) A novel quantitative fluorescent reporter assay for RAG targets and RAG activity

    Frontiers in Immunology 4:110.

    https://doi.org/10.3389/fimmu.2013.00110

    • PubMed
    • Google Scholar
97. 1. Tsubata T
    2. Reth M

    (1990) The products of pre-B cell-specific genes (lambda 5 and VpreB) and the immunoglobulin mu chain form a complex that is transported onto the cell surface

    The Journal of Experimental Medicine 172:973–976.

    https://doi.org/10.1084/jem.172.3.973

    • PubMed
    • Google Scholar
98. 1. Tsubata T

    (2020) Involvement of reactive oxygen species (ROS) in BCR signaling as a second messenger

    Advances in Experimental Medicine and Biology 1254:37–46.

    https://doi.org/10.1007/978-981-15-3532-1

    • Google Scholar
99. 1. Tzur A
    2. Moore JK
    3. Jorgensen P
    4. Shapiro HM
    5. Kirschner MW

    (2011) Optimizing optical flow cytometry for cell volume-based sorting and analysis

    PLOS ONE 6:e16053.

    https://doi.org/10.1371/journal.pone.0016053

    • PubMed
    • Google Scholar
100. 1. Vandenberg CJ
     2. Josefsson EC
     3. Campbell KJ
     4. James C
     5. Lawlor KE
     6. Kile BT
     7. Cory S

     (2014) Loss of Bak enhances lymphocytosis but does not ameliorate thrombocytopaenia in BCL-2 transgenic mice

     Cell Death and Differentiation 21:676–684.

     https://doi.org/10.1038/cdd.2013.201

     • PubMed
     • Google Scholar
101. 1. Vela JL
     2. Aït-Azzouzene D
     3. Duong BH
     4. Ota T
     5. Nemazee D

     (2008) Rearrangement of mouse immunoglobulin kappa deleting element recombining sequence promotes immune tolerance and lambda B cell production

     Immunity 28:161–170.

     https://doi.org/10.1016/j.immuni.2007.12.011

     • PubMed
     • Google Scholar
102. 1. Verkoczy L
     2. Aït-Azzouzene D
     3. Skog P
     4. Märtensson A
     5. Lang J
     6. Duong B
     7. Nemazee D

     (2005) A role for nuclear factor kappa B/rel transcription factors in the regulation of the recombinase activator genes

     Immunity 22:519–531.

     https://doi.org/10.1016/j.immuni.2005.03.006

     • PubMed
     • Google Scholar
103. 1. Wardemann H
     2. Hammersen J
     3. Nussenzweig MC

     (2004) Human autoantibody silencing by immunoglobulin light chains

     The Journal of Experimental Medicine 200:191–199.

     https://doi.org/10.1084/jem.20040818

     • Google Scholar
104. 1. Wheeler ML
     2. Defranco AL

     (2012) Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation

     Journal of Immunology 189:4405–4416.

     https://doi.org/10.4049/jimmunol.1201433

     • PubMed
     • Google Scholar
105. 1. Xu S
     2. Lee KG
     3. Huo J
     4. Kurosaki T
     5. Lam KP

     (2007) Combined deficiencies in Bruton tyrosine kinase and phospholipase Cγ2 arrest B-cell development at a pre-BCR+ stage

     Blood 109:3377–3384.

     https://doi.org/10.1182/blood-2006-07-036418

     • Google Scholar
106. 1. Yabas M
     2. Teh CE
     3. Frankenreiter S
     4. Lal D
     5. Roots CM
     6. Whittle B
     7. Andrews DT
     8. Zhang Y
     9. Teoh NC
     10. Sprent J
     11. Tze LE
     12. Kucharska EM
     13. Kofler J
     14. Farell GC
     15. Bröer S
     16. Goodnow CC
     17. Enders A

     (2011) ATP11C is critical for the internalization of phosphatidylserine and differentiation of B lymphocytes

     Nature Immunology 12:441–449.

     https://doi.org/10.1038/ni.2011

     • Google Scholar
107. 1. Yasuda T
     2. Sanjo H
     3. Pagès G
     4. Kawano Y
     5. Karasuyama H
     6. Pouysségur J
     7. Ogata M
     8. Kurosaki T

     (2008) Erk kinases link pre-B cell receptor signaling to transcriptional events required for early B cell expansion

     Immunity 28:499–508.

     https://doi.org/10.1016/j.immuni.2008.02.015

     • PubMed
     • Google Scholar
108. 1. Zelazowska MA
     2. Dong Q
     3. Plummer JB
     4. Zhong Y
     5. Liu B
     6. Krug LT
     7. McBride KM

     (2020) Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire

     Life Science Alliance 3:e201900526.

     https://doi.org/10.26508/lsa.201900526

     • PubMed
     • Google Scholar
109. 1. Zhang K
     2. Sun W
     3. Liu Y
     4. Lv Y
     5. Hou D
     6. Lin Y
     7. Xu W
     8. Zhao J
     9. Gai Z
     10. Zhao S
     11. Yuan Y

     (2021) SINO syndrome causative KIDINS220/ARMS gene regulates adipocyte differentiation

     Frontiers in Cell and Developmental Biology 9:619475.

     https://doi.org/10.3389/fcell.2021.619475

     • PubMed
     • Google Scholar

Author details

1. Anna-Maria Schaffer

   1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
   2. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
   3. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Validation, Investigation, Visualization, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-2561-0820

2. Gina Jasmin Fiala

   1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
   2. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
   3. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

3. Miriam Hils

   1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
   2. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany
   3. Department of Dermatology and Allergy Biederstein, School of Medicine, Technical University of Munich, Munich, Germany

   Contribution

   Data curation, Investigation, Visualization

   Competing interests

   No competing interests declared

4. Eriberto Natali

   Institute of Medical Engineering and Medical Informatics, School of Life Sciences, FHNW 15 University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland

   Contribution

   Software, Formal analysis, Visualization

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9100-807X

5. Lmar Babrak

   Institute of Medical Engineering and Medical Informatics, School of Life Sciences, FHNW 15 University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland

   Contribution

   Data curation, Software, Formal analysis, Investigation, Visualization

   Competing interests

   No competing interests declared

6. Laurenz Alexander Herr

   1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
   2. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
   3. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1035-2558

7. Mari Carmen Romero-Mulero

   1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
   2. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

   Contribution

   Formal analysis

   Competing interests

   No competing interests declared

8. Nina Cabezas-Wallscheid

   1. Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany
   2. CIBSS – Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany

   Contribution

   Supervision, Investigation

   Competing interests

   No competing interests declared

9. Marta Rizzi

   1. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany
   2. CIBSS – Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
   3. Division of Clinical and Experimental Immunology, Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
   4. Department of Rheumatology and Clinical Immunology, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

   Contribution

   Conceptualization, Supervision, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

10. Enkelejda Miho

    1. Institute of Medical Engineering and Medical Informatics, School of Life Sciences, FHNW 15 University of Applied Sciences and Arts Northwestern Switzerland, Muttenz, Switzerland
    2. aiNET GmbH, Basel, Switzerland
    3. SIB Swiss Institute of Bioinformatics, Lausanne, Switzerland

    Contribution

    Conceptualization, Formal analysis, Supervision, Investigation

    Competing interests

    owns shares in aiNET GmbH

11. Wolfgang WA Schamel

    1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
    2. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    3. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany

    Contribution

    Conceptualization, Supervision, Funding acquisition, Investigation, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0003-4496-3100

12. Susana Minguet

    1. Faculty of Biology, Albert-Ludwigs-University of Freiburg, Freiburg, Germany
    2. Signalling Research Centers BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
    3. Center of Chronic Immunodeficiency CCI, University Clinics and Medical Faculty, Freiburg, Germany

    Contribution

    Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Visualization, Writing – original draft, Project administration, Writing – review and editing

    For correspondence

    susana.minguet@biologie.uni-freiburg.de

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-8211-5538

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