Genes are turned into their protein products via two steps. The first, transcription, produces an intermediate RNA molecule or ‘transcript’; the second step, translation, turns the transcript into a protein. Most genes in mammals contain stretches of DNA called exons, which code for protein, interspersed with sequences called introns that do not. Therefore, a transcript must be ‘spliced’ before translation—the introns are removed and the exons joined.

In some genes, certain exons can be optionally included or excluded from a transcript to produce different versions of the same protein that can often have very different functions. This is known as alternative splicing, and is essential for normal development. A large number of regulatory proteins control this process, many of which are only made in specific types of cells or tissues.

Esrp1 and Esrp2 are two proteins that regulate alternative splicing in epithelial cells. These specialized cells form sheets that line most organs in the body and are found in the epidermis, the outermost layer of the skin. Although Esrp1 and Esrp2 have previously been studied in the laboratory using cultured cell lines, their roles have not been investigated in living animals.

Bebee, Park et al. have now examined mice that are unable to produce one or both of these proteins. Mice that only lacked Esrp1 developed a cleft lip and palate. In mice that lacked both proteins, many organs failed to develop correctly and in some cases did not form at all. In the epidermis, the loss of Esrp1 and Esrp2 disrupted the splicing of the transcripts from genes that give epithelial cells many of their specialized characteristics, such as the ability to form sheets of cells with well formed junctions between them. This meant that epidermis that lacked Esrp1 and Esrp2 could not form a proper barrier layer, which is a crucial role of epithelia in skin as well as in other organs.

In future, the mutant mice will be valuable for exploring how alternative splicing affects the development of epithelial cells and their properties.

Alternative splicing (AS), the differential incorporation of exons into a mature mRNA transcript, is a widespread mechanism of generating multiple mRNAs from a single gene (Chen and Manley, 2009; Kalsotra and Cooper, 2011; Fu and Ares, 2014). The result of AS is the proteomic expansion of an otherwise limited genome. Switches in mRNA isoforms due to AS often result in protein isoforms with distinct functions essential for normal development, and dysregulated splicing of these events can lead to disease (Moroy and Heyd, 2007; Singh and Cooper, 2012; Kelemen et al., 2013; Cieply and Carstens, 2015). Indeed, over 95% of multi-exon genes in humans are alternatively spliced and AS has been shown to have essential functions across vertebrate and invertebrate lineages (Graveley, 2001; Pan et al., 2008; Wang et al., 2008). AS is regulated by a balance of positive and negatively acting RNA binding proteins (RBPs) that can alter the recruitment of the spliceosome, the macromolecular RNA-protein complex required for splicing, to the 5′ and 3′ splice sites in a pre-mRNA. Regulatory splicing factors are accessory RBPs which are often not components of the spliceosome, but that associate with a subset of transcripts via interactions with cognate RNA binding sites within exons and introns of the pre-mRNA. In many cases the position of the regulatory splicing factors relative to one another and to the alternatively spliced exon determine whether they promote splicing or skipping of a given exon (Fu and Ares, 2014). In addition to the accessory RNA splicing factors, core spliceosomal proteins can also modulate the efficiency of exon recognition and in turn modify AS (Park et al., 2004; Saltzman et al., 2011).

There are several classes of regulatory splicing factors including the well-described serine/arginine rich (SR) proteins and heterogeneous nuclear ribonucloproteins (hnRNPs), which are largely ubiquitously expressed (Fu and Ares, 2014). However, a growing number of cell- and tissue-type-specific splicing factors have been identified, which regulate global splicing regulatory networks (SRNs) that converge on functionally coherent biological pathways required for the cell or tissue in which they are expressed (Ule et al., 2005; Kalsotra et al., 2008; Warzecha et al., 2009a; Gehman et al., 2011; Licatalosi et al., 2012; Quesnel-Vallieres et al., 2015). Transcripts that are alternatively spliced as part of tissue- or cell-type specific SRNs do not significantly overlap with transcriptional gene expression programs in the same tissues or cells, indicating that AS and transcriptional regulation are largely independent processes utilized to diversify the transcriptomes that distinguish different cell types (Pan et al., 2008). This observation thus highlights the function of AS as an added layer of gene expression regulation, as well as the potential role of AS in fine tuning the functions of proteins in biological pathways relevant to different cell types. Tissue- or cell-type-specific regulatory splicing factors and the programs of AS under their control are often required during normal development, which has been most extensively characterized in brain, muscle, and cardiac tissue (Kalsotra et al., 2008; Gehman et al., 2011; Licatalosi et al., 2012; Lee et al., 2013; Li et al., 2014; Yang et al., 2014; Quesnel-Vallieres et al., 2015). The bulk of tissue-specific splicing factors have been identified in these organ systems, and in turn the requirement of tissue specific AS in cardiac, neural, and muscle development has been further characterized in mouse models. The loss of regulatory splicing factors in these tissues often result in defects in fetal to adult splicing transitions, tissue patterning defects, and organ dysfunction (Licatalosi et al., 2012; Li et al., 2014; Yang et al., 2014). Tissue and/or cell-type-specific networks of AS contribute to the posttranscriptional landscape of a tissue or cell type, generating splicing isoforms that provide specific functions in the tissue or cell in which they are generated (Castle et al., 2008). It is important to recognize that most human and mouse tissues and organs are comprised of numerous distinct cell types. These cell types within tissues include endothelial, epithelial, and fibroblast cells that express common splicing patterns independent of the tissue of origin (Mallinjoud et al., 2014). This further emphasizes the role of cell type- or tissue-specific AS outside of the nervous system, muscle, and cardiac tissues as well as within defined cell types. As such there remain many gaps in our understanding of distinct cell type-specific programs of AS that differ both between and within different tissues.

The requirement of regulatory splicing factors in normal development underscores the requirement of AS and the protein isoforms generated therein in normal patterning and development. One example of a cell-type-specific splicing event that is essential for normal development is AS of the Fibroblast growth factor receptor 2 (Fgfr2) pre-mRNA, where there is distinct expression of the Fgfr2-IIIb or Fgfr2-IIIc isoform in epithelial and mesenchymal cells, respectively (Orr-Urtreger et al., 1993). The mutually exclusive AS of exons IIIb and IIIc alters the second half of the Immunoglobulin-like III (Ig3) domain of the receptor extracellular ligand binding domain, and in turn alters the binding specificity of the Fgfr2 receptor to its cognate Fgf ligands (Zhang et al., 2006). The exquisite cell-type-specific expression of the Fgfr2-IIIb and Fgfr2-IIIc isoforms underlies reciprocal communication between epithelium and neighboring mesenchyme, wherein the ability of the epithelial Fgfr2-IIIb receptor to respond to mesenchymally expressed Fgfs, and vice versa, has proven essential for the development of multiple organs and appendages during embryogenesis. Knockout (KO) of Fgfr2-IIIb or one of its primary ligands, Fgf10, in mouse results in developmental defects in limb, lung, craniofacial and palate formation, salivary gland, tooth, and epidermal appendage (hair) formation (Xu et al., 1998; De Moerlooze et al., 2000; Ohuchi et al., 2000; Revest et al., 2001; Petiot et al., 2003). This highlights the crucial function of this signaling axis in normal patterning during development in a wide range of cells and tissues. Moreover, the AS of Fgfr2-IIIb/c has also been shown to dynamically change during the cellular transformation process of epithelial to mesenchymal transition (EMT), a necessary developmental process for embryo and tissue morphogenesis (Savagner et al., 1994; Thiery et al., 2009).

Given the distinct cell type-specific splicing of Fgfr2 transcripts and well outlined functional consequences we and others sought to define the cis- and trans-acting determinants of this AS event (Carstens et al., 2000; Hovhannisyan and Carstens, 2005; Mauger et al., 2008). Using a genome-wide high-throughput cDNA screen we identified the epithelial splicing regulatory proteins 1 and 2 (Esrp1 and Esrp2) as essential regulators of Fgfr2 splicing (Warzecha et al., 2009a). The expression of the ESRPs (ESRP1 and ESRP2) is epithelial cell type-specific and knockdown of ESRP1 and ESRP2 in epithelial cells induces a complete switch from Fgfr2-IIIb to Fgfr2-IIIc isoforms. Conversely, ectopic expression of Esrp1 in mesenchymal cells induces a switch from Fgfr2-IIIc to Fgfr2-IIIb, indicating that the ESRPs are necessary and sufficient to enforce expression of the epithelial Fgfr2-IIIb isoform (Warzecha et al., 2009a). Using splicing sensitive microarrays and high throughput sequencing (RNA-seq), we previously used cell lines to demonstrate that the ESRPs control a genome-wide program of AS (Warzecha et al., 2009b, 2010; Dittmar et al., 2012). Importantly, ESRP targets are enriched for genes involved in epithelial cell properties such as cytoskeletal dynamics, cell motility, cell–cell junctions, and pathways involved in EMT. These observations strongly suggested that genome-wide programs of ESRP regulated splicing coordinate biological functions necessary for normal development and epithelial cell function (Warzecha et al., 2009b, 2010; Dittmar et al., 2012).

While we previously used cell culture based systems to define the targets and functions of the ESRPs in vitro, a definitive investigation of their functions during development and identification of targets in vivo was needed. The ESRP mouse homologues, Esrp1 and Esrp2, are specifically expressed in epithelial cells in numerous organs in adult mice and are essentially absent in mesenchymal cells and other non-epithelial cell types (Figure 1—figure supplement 1). For example, our previous RNA in situ RNA analysis for Esrp1 and similar in situ analysis for Esrp2 presented here document expression of both mRNAs in all epithelial cell layers that comprise the epidermis as well as epithelial cells of the lung, large and small intestine, salivary glands, bladder, kidney, and other prototypical epithelial cell layers (Figure 1—figure supplement 1B–D, also see Figures S5–S8 in Warzecha et al. (2009a)). Furthermore, in situ analysis of Esrp1 expression during mouse embryogenesis demonstrated specific Esrp1 expression in definitive endoderm and surface ectoderm as well as epithelial cells derived from these germ layers (Revil and Jerome-Majewska, 2013). Comprehensive microarray analysis in mouse tissues and cells has also documented the expression of both Esrp1 and Esrp2 in distinct tissues and cell types (Figure 1—figure supplement 1A) (Su et al., 2002). To address the functional requirement of the Esrps in development we generated Esrp1 and Esrp2 KO mice. Whereas Esrp2 null mice are viable and fertile, we demonstrate that KO of Esrp1 alone is neonatal lethal at Postnatal Day (P) 0, associated with fully penetrant bilateral cleft lip and palate (CL/P). Esrp1 KO combined with loss of Esrp2 resulted in more pronounced defects in organogenesis that will be described herein. For the first in vivo evaluation of a global Esrp-regulated AS program we utilized total epidermis for RNA-seq. The loss of Esrps in epidermis is also associated with global changes in gene expression indicative of an epithelial barrier defect. We confirmed this skin barrier defect using conditional KO of the Esrps in epidermis. The Esrp KO mice reveal the essential role of the Esrps in maintaining an epithelial cell-specific splicing program for normal development during mouse embryogenesis, underscoring the role of AS in the development of a multitude of organs and appendages, and the requirement of the Esrps in critical epithelial cell functions.

This study represents the first in vivo analysis of the epithelial-specific splicing factors, Esrp1 and Esrp2 and the broad roles they play in epithelial cells in a multitude of organs. The numerous developmental defects we identified in these mice demonstrate an essential role for Esrp-regulated splicing in the development of many organ systems. Using germline KOs for Esrp1 and Esrp2 we demonstrate a requirement for Esrp1 during embryonic development and postnatal survival, with loss of both proteins manifesting the most severe phenotypes. To evaluate Esrp regulated splicing in the context of the development of a specific tissue we used the readily accessible epidermis as our model system. We uncovered variable sensitivity of AS events to loss of Esrp1 alone or in combination with loss of Esrp2, which were also enriched for Esrp binding motifs. Global changes in gene expression accompanying loss of the Esrps in the skin of the germline DKO mice revealed an epidermal barrier defect that was confirmed using conditional ablation of the Esrps in the epithelial cells that constitute the epidermis. Together, these observations provide strong evidence for the cell autonomous requirement of the Esrps in epidermal development and programs of epithelial-specific splicing in organogenesis and epithelial cell function.

The characterization of Esrp deficient embryos revealed striking defects in several organ systems. The primary and most readily apparent defect in mice with ablation of Esrp1 alone was fully penetrant bilateral cleft lip and palate (CL/P). Orofacial defects are amongst the most common forms of birth defects but the causes of CL/P are heterogeneous, including syndromic and non-syndromic genetic disorders and environmental factors (Dixon et al., 2011). Importantly, whereas there are greater numbers of patients that have cleft lip with or without cleft palate (CL/P) compared to isolated cleft palate (Cleft Palate Only [CPO]), there are few mouse models for CL/P compared to CPO. The limited mouse models for CL/P include KO models for genes regulating signaling and transcription (Juriloff and Harris, 2008). Therefore, the Esrp KO mouse is a unique model that can be used to further evaluate the role of epithelial-specific splicing regulation in lip and palate formation. Based on previous evidence that cell or tissue-specific splicing factors regulate biologically coherent sets of targets genes in the cells that express them, further determination of epithelial specific splice variants could provide molecular insights into novel genes underlying the pathogenesis of CL/P. The orofacial defects were more severe in mice with combined loss of Esrp2. Similarly, mice deficient for Esrp1 and Esrp2 exhibit progressively more severe phenotypes in other organs and tissues, including forelimb, salivary gland, lung, and skin. The functional redundancy of the Esrps during development is consistent with our in vitro observations at the level of AS. Therefore, the progression of phenotypes could be due to the degree of change in AS mediated by loss of Esrp1 alone or in combination with Esrp2.

To evaluate the potential for Esrp1 and Esrp2 co-regulation of AS, we used the epidermis as our model system to identify the global Esrp regulated splicing program in vivo. We illustrated the possible biological impact of varied sensitivity of Esrp targets by highlighting the splicing of exons -IIIb and -IIIc in the Fgfr family of receptors. This splicing event regulates ligand binding specificity and the Fgf signaling axis is a crucial signaling pathway utilized during development in a multitude of organ systems. It is of note that despite the fact that the Esrps are required for expression of Fgfr2-IIIb, Esrp DKO embryos do not fully phenocopy the defects previously seen in Fgfr2-IIIb KO mice. This is most evident in the craniofacial and limb defects, where KO of Esrp1 alone results in bilateral cleft lip and palate and DKO embryos have forelimb defects, whereas Fgfr2-IIIb KO mice exhibit CPO and absence of both forelimbs and hindlimbs (De Moerlooze et al., 2000; Rice et al., 2004). Part of this discrepancy can likely be accounted for by differences in the manner in which Fgfr2 splicing is altered in each model. In our mice, there is a switch in splicing from exon IIIb to IIIc in Esrp DKO mice that would still encode a functional receptor, albeit one with altered ligand binding specificities. In contrast, the deletion of exon IIIb in Fgfr2-IIIb KO mice does not result in default splicing to exon IIIc in epithelial cells, but instead results primarily in skipping of both exons IIIb and IIIc, thereby inactivating Fgfr2 expression altogether in epithelial cells, but retaining Fgfr2-IIIc in mesenchymal cells. Hence in some contexts, autocrine or paracrine functions of Fgf ligands for Fgfr2-IIIc may compensate for the switch in Fgfr2 splicing, but not in others. For example, ablation of Fgfr2-IIIb and its mesenchymal derived ligand Fgf10, result in failure to form lungs and submandibular (salivary) glands, indicating that the switch in Fgfr2 isoforms in Esrp DKO mice may be sufficient to phenocopy these defects, but not others. However, it must also be emphasized that Esrp ablation also induces global changes in AS that surely contribute to the phenotypes we observe, including those, such as cleft lip, that were not identified in Fgfr2-IIIb KO mice. In the epidermis, we suspect that alterations in Fgf receptor splicing and Fgf signaling contribute to the phenotypes we observed since epidermal hypoplasia was observed in both Fgfr2-IIIb and Esrp1/Esrp2 DKO skin. However, conditional KO of Fgfr2-IIIb as well as combined KO of Fgfr2 and Fgfr1-IIIb in the epidermis is not lethal unlike the post-natal lethality we observe when Esrp1 and Esrp2 are conditionally ablated in epidermis. While skin from mice with epidermal-specific ablation of Fgfr2-IIIb or Fgfr2/Fgfr1-IIIb exhibits some inflammation and/or a later onset barrier defect in adult skin, these mice survive for at least several months post-natally. These observations, combined with the fact that Esrp1/Esrp2 ablation in the epidermis is associated with an isoform switch rather than complete loss of function of Fgfr1 and Fgfr2 receptor proteins, strongly suggest that splicing changes in additional Esrp target transcripts are required for the lethal barrier defect we observe. Therefore, the challenge for future studies will be to identify the individual or combined splicing events that underlie the observed phenotypes in the skin as well as other tissues and organs.

In many of the Esrp targets we identified large ‘switch-like’ changes in AS with the loss of the Esrps. These changes would lead to an altered proteomic landscape by the loss or introduction of different protein isoforms. For example, Fgfr2 undergoes a full switch from -IIIb to -IIIc, thus entirely swapping one isoform for its alternative isoform. We also observed cases where the loss of the Esrps resulted in the loss of an isoform or the inverse where a new isoform was introduced (e.g.,: Fgfrs, Enah, Arhgef11, Itga6, Macf1, Nf2, etc). These changes in protein isoforms likely underlie the observed phenotypes in the Esrp deficient mice. The variable sensitivity of AS events to the loss of Esrp1 vs combined loss of Esrp1 and Esrp2 was not restricted to a handful of Esrp targets, but rather was observed in the global splicing analysis in the epidermis. The fact that Esrp2 can only partially compensate for loss of Esrp1 in the epidermis, despite retaining high expression in Esrp1 KO mice, indicates that this differential sensitivity partly reflects reduced splicing activity of Esrp2 compared to Esrp1. It is important to emphasize that the levels of both Esrp1 and Esrp2 expression are high in the epidermis (Average FPKM: Esrp1 130, Esrp2 127), which in turn could impart greater functional redundancy in the epidermis. However, not all epithelial cells express Esrp1 or Esrp2 as highly as in the skin and most epithelial cells express less Esrp2 relative to Esrp1 (Su et al., 2002). The differences in phenotypes observed in the Esrp1 KO and Esrp1/Esrp2 DKO may therefore reflect splicing alteration in specific transcripts for which Esrp2 cannot fully compensate for loss of Esrp1 and/or be reflective of differences in Esrp2 levels in different epithelia.

To determine a potential mechanism underlying the varied AS sensitivity we mapped Esrp RNA binding motifs for the SE cassette exons using the GU-rich sequences identified by SELEX-Seq (Dittmar et al., 2012). The SE events identified from the KO epidermis were enriched for Esrp binding motifs in the upstream intron and exon body of silenced exons, and within the downstream intron of enhanced exons proximal to the 5′ splice site. This RNA binding map is consistent with strong repression and enhancement, respectively. This motif enrichment pattern is most strikingly observed in the KO dataset, as the exon body enrichment is reduced/lost in the KH and DKO samples. This describes a potential mechanism in which the Esrp1 KO sensitive AS events require more Esrp binding sites for maintenance of the Esrp-directed splicing pattern. In the absence of Esrp1 expression, Esrp2 is not sufficient to drive AS regulation or to block the activity of other splicing factors that promote the opposite pattern of splicing. Despite the absence of major changes in gene expression of other splicing factors, it is likely that other splicing factors contribute to the regulation of Esrp AS targets. RBFOX2 has been shown to co-regulate ESRP AS events, including those associated with EMT, despite only small changes in RBFOX2 expression in EMT (Dittmar et al., 2012). Similarly the ubiquitously expressed hnRNPM was shown to regulate splicing of CD44 during EMT, but only in conjunction with down regulation of the Esrps (Xu et al., 2014).

The Esrps direct a program of AS that is highly conserved between human and mouse and enriched in biologically coherent pathways involved in epithelial cell biology and function. The Esrps are also highly conserved in the three RRMs in the orthologous Fusilli in fruit flies (Drosophila melanogaster) and Sym-2 in round worm (Caenorhabditis elegans). We have shown that Fusilli is partially functional in directing ESRP splicing events when transfected in human cells lacking the ESRPs, indicating clear conservation of function (Warzecha et al., 2009a). The expression of Fusilli is also epithelial-specific and both Fusilli and Sym-2 have been shown to function as a regulator of endogenous AS in Drosophila cells and C. elegans, respectively (Wakabayashi-Ito et al., 2001; Barberan-Soler and Zahler, 2008) (unpublished data). In Drosophila, Fusilli homozygous mutation was lethal, indicating that Esrp and Fusilli are both essential splicing factors despite substantial phylogenetic distance between mammals and flies. Although the genomic architecture of fly and worm genes differ greatly from higher eukaryotes, precluding direct comparison of splicing events, it will be interesting to further explore whether these evolutionarily conserved orthologues of the Esrps also regulate programs of splicing that function in similar processes and pathways.

The epidermis served as a model to evaluate epithelial cell function, as the skin serves as the primary defense to the external environment as well as maintaining fluid homeostasis. The increase in EDC gene expression in the DKO epidermis is likely an indirect effect of the loss of the Esrps, but in turn it implicates Esrp regulated splicing in the maintenance of epithelial cell function necessary for barrier function in vivo. For example, we confirmed the differential splicing of several genes that have been evaluated in KO mice for skin barrier function and maturation of cellular junctions. Nf2 (Merlin) exhibited a ‘switch-like’ change in AS in the DKO epidermis, transitioning from nearly full inclusion to full skipping (Figure 4B). Similar to our Krt14-DKO mice, conditional ablation of Nf2 using Krt14-Cre resulted in mice with dry, flaky skin, and epidermal barrier defects as measured by water loss assay. Biochemical evaluation identified Nf2 as an interaction partner with the adherens junction (AJ) and Par3 necessary for the maturation of AJ to mature TJs (Gladden et al., 2010). While this analysis was performed in complete KO of Nf2, evaluating the isoform specific functions of Nf2 under regulation by the Esrps could provide further insight into the maturation of junctional complexes required for epithelial cells and barrier function. The Esrps directly regulate the levels of Grhl1 by promoting exon 5 inclusion and preventing transcript degradation by NMD. Mice lacking Grhl1 have reduced expression of desmosomal cadherins resulting in mild anchoring defects of hair follicles in the skin (Wilanowski et al., 2008). Epidermal barrier defects by way of epidermal hyperplasia and inflammatory cell infiltration were observed in adult mice lacking Grhl1 (Mlacki et al., 2014). Cd44 has a complex pattern of splicing in which the variable region encoded by 10 exons is included in epithelial cells, and skipping of these exons is observed in non-epithelial cells. Mice lacking Cd44, which in the case of the epidermis is the Esrp regulated epithelial form Cd44v, have delays in outside-in barrier formation during embryonic development and barrier formation measured in cultured keratinocytes (Kirschner et al., 2011). These examples of Esrp splicing targets involved in skin barrier function highlight the roles of the Esrps in regulating known genes involved in this process. Defects in epithelial barrier function are associated with human disorders in multiple organs including atopic dermatitis, allergen response in respiratory tracts, and gastrointestinal inflammation (Segre, 2006). We predict that numerous Esrp-regulated targets will also be shown to play roles in epithelial barrier function in the skin and other epithelial populations. Thus, the Esrp DKO mice can be used to evaluate isoform-specific functions of known barrier genes, as well as identify novel genes involved in the maintenance of epithelial barrier function via functions of epithelial specific protein isoforms.

The KO of the Esrp proteins in mice provides the first evidence for a requirement for these cell-type-specific splicing factors in embryonic development and epithelial cell functions. The identification of the Esrp regulated splicing program provides numerous examples of genes that merit further investigation into their developmental functions and contribution to human diseases such as CL/P and diseases associated with epithelial barrier defects. A challenge for future studies will be to functionally dissect the molecular mechanisms by which some of these isoform-specific activities are involved in maintenance not only of epithelial barriers, but also in mediating epithelial-mesenchymal crosstalk during development and maintaining other properties of epithelial cells. The compilation of Esrp regulated in vivo splicing targets in tissue-specific epithelial populations will provide further insights into the posttranscriptional splicing networks in epithelial cells at play during development and organogenesis of various tissues.

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Author details

1. Thomas W Bebee

   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   TWB, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Juw Won Park

   Competing interests

   The authors declare that no competing interests exist.

2. Juw Won Park

   Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States

   Present address

   Computer Engineering and Computer Science, Kentucky Biomedical Research Infrastructure Network, University of Louisville, Louisville, United States

   Contribution

   JWP, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   Contributed equally with

   Thomas W Bebee

   Competing interests

   The authors declare that no competing interests exist.

3. Katherine I Sheridan

   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   KIS, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

4. Claude C Warzecha

   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   CCW, Acquisition of data, Analysis and interpretation of data, Contributed unpublished essential data or reagents

   Competing interests

   The authors declare that no competing interests exist.

5. Benjamin W Cieply

   Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   BWC, Acquisition of data, Drafting or revising the article

   Competing interests

   The authors declare that no competing interests exist.

6. Alex M Rohacek

   Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   AMR, Acquisition of data, Analysis and interpretation of data

   Competing interests

   The authors declare that no competing interests exist.

7. Yi Xing

   Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States

   Contribution

   YX, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   yxing@ucla.edu

   Competing interests

   The authors declare that no competing interests exist.

8. Russ P Carstens

   1. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
   2. Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

   Contribution

   RPC, Conception and design, Acquisition of data, Analysis and interpretation of data, Drafting or revising the article

   For correspondence

   russcars@upenn.edu

   Competing interests

   The authors declare that no competing interests exist.

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