Wolbachia are a bacterial endosymbiont present in the majority of insect species (Weinert et al., 2015; Werren et al., 2008). While they reside in the germline of both sexes, they are vertically transmitted exclusively through the female germline to all the offspring (Kaur et al., 2021). Consequently, Wolbachia have evolved a number of strategies that provide a selective advantage to infected females. This includes male killing, conversion of males to fertile females, induction of parthenogenesis, and most commonly cytoplasmic incompatibility (CI) (Serbus et al., 2008). CI is a form of Wolbachia-induced paternal effect embryonic lethality. Matings between infected males and uninfected females result in dramatic reductions in egg hatch rates (Hoffmann et al., 1986). However, matings between infected males and infected females, known as the ‘rescue cross’, results in normal egg hatch rates. Additionally, infected females mated with uninfected males results in normal hatch rates. Thus, in a Wolbachia-infected population, infected females have an enormous selective advantage over uninfected females as infected females produce normal hatch rates independent of the infection status of the male (Turelli and Hoffmann, 1991). This phenomenon, as well as Wolbachia-induced male sterility, is currently being employed throughout the world as a strategy for combating pest insects and insect-borne human diseases (Jiggins, 2017; Moretti et al., 2018; Zheng et al., 2019).

Since the discovery of CI and rescue (Ghelelovitach, 1952; Yen and Barr, 1971), there have been a number of insights into their molecular and cellular bases (Shropshire et al., 2020). Cytological studies demonstrate failures in condensation, alignment, and segregation of the paternal chromosomes during the first zygotic division in embryos derived from the CI cross (Breeuwer and Werren, 1990; Callaini et al., 1997; Lassy and Karr, 1996; Reed and Werren, 1995; Ryan and Saul, 1968; Tram et al., 2006; Tram and Sullivan, 2002). Subsequent studies demonstrated defects in the protamine-to-histone transition: deposition of the maternally supplied histone H3.3 is significantly delayed (Landmann et al., 2009). In addition, the male, but not the female, pronucleus of CI-derived embryos exhibits delays in DNA replication, nuclear envelope breakdown, and Cdk1 activation (Tram and Sullivan, 2002). As a result, passage of the male pronucleus through mitosis is delayed relative to the female pronucleus. Molecular insight into the mechanism of CI has come from recent studies demonstrating that a pair of Wolbachia genes originating from integrated viral DNA, the CI factors or Cifs, is likely responsible for CI (Beckmann et al., 2017; LePage et al., 2017). One of these genes, cidB, encodes a deubiquitylating enzyme and the other, cinB, a nuclease (Chen et al., 2020). When the gene pair is expressed in the male germline, paternal chromosome, and embryo abnormalities strikingly similar to Wolbachia-mediated CI are observed (Beckmann et al., 2017; LePage et al., 2017).

In addition to the well-characterized first division mitotic defects, studies in a number of species demonstrate that CI produces additional developmental defects and lethal phases later in embryogenesis (Bonneau et al., 2018; Callaini et al., 1997; Callaini et al., 1996; Duron and Weill, 2006; Jost, 1970; Lassy and Karr, 1996; Wright and Barr, 1981). Studies in wasps in which fertilized eggs develop into diploid females and unfertilized eggs develop into haploid males, provide insight into the different developmental outcomes in CI crosses (Tram et al., 2006). If CI disrupts but does not prevent paternal chromosome segregation, the resulting aneuploid embryos fail to develop. In contrast, if CI results in the complete failure of paternal chromosome segregation, embryos develop into haploid males bearing only the maternal chromosome complement (Ryan and Saul, 1968; Tram et al., 2006). In diplo-diploid organisms (where haploid embryos do not develop to adulthood), complete failure of paternal chromosome segregation in the first division leads to haploid embryos that develop and then subsequently fail to hatch (Bonneau et al., 2018; Callaini et al., 1997; Callaini et al., 1996; Duron and Weill, 2006; Jost, 1970). Additionally, in some organisms such as Drosophila simulans, a small fraction of CI-derived embryos do not undergo any first division defect and consequently hatch as diploids (Lassy and Karr, 1996).

In conjunction with broad developmental abnormalities, embryos developing from CI crosses also experience various cellular defects (Callaini et al., 1996). For example, studies in Drosophila have observed chromosome bridging in CI-derived embryos developing through the pre-blastoderm divisions (nuclear cycles 2–9) (Lassy and Karr, 1996; LePage et al., 2017). Additionally, irregular spindles are observed in syncytial and cellularized blastoderms (nuclear cycles 10–14) from CI crosses (Callaini et al., 1996). Other defects in developed embryos from CI crosses include displaced nuclei, clumped chromatin, and disorganized centrosomes in blastoderms and abnormally condensed nuclei in gastrulating embryos (Callaini et al., 1996). However, due to inherent difficulties in visualizing fertilization and early embryonic development in Drosophila, whether the cellular defects observed in later stage embryos are the direct result of aneuploidy from first division errors or due to a poorly understood second, distinct set of CI-induced defects remained unresolved. Therefore, the extent and timing with which CI induces cellular defects throughout development is an open question.

Here, through a combination of live and fixed analysis, we directly address whether late developmental and cellular defects observed in CI-derived embryos are an outcome of the well-characterized first division errors or caused by a temporally distinct set of CI-induced cell cycle defects. Consistent with previous reports, we find that the majority of embryos derived from the CI cross arrest in the first division. However, we specifically focus our analyses on a population of about one-third of CI-derived embryos that apparently progress normally through the first zygotic and subsequent internal syncytial divisions. While these embryos undergo normal pre-blastoderm divisions, they exhibit significantly increased chromosome segregation defects during the mid-blastula transition, cellularization, and gastrulation. Sequence analysis reveals that ~40% of the CI-derived embryos that reach the blastoderm stage (>nuclear cycle 10) are diploid, having undergone a normal first division to develop with both maternal and paternal chromosomes. Using fluorescence in situ hybridization (FISH) to specifically select these diploid CI-derived embryos, we observe increased chromosome segregation defects during gastrulation, suggesting the late embryonic defects do not strictly require significant first division defects. Crosses to infected females (the rescue cross) reduce the frequencies of the induced division errors. These results reveal that Wolbachia CI-induced defects in the sperm produce developmentally deferred chromosome segregation defects in the late blastoderm divisions. Thus, our studies suggest CI produces temporally distinct early and late chromosome segregation defects. These findings provide insight into the mechanisms and timing of CI.

In addition to the well-characterized early embryonic arrest, a number of reports reveal a large portion of CI-derived embryos undergo substantial embryonic development but then fail to hatch (Bonneau et al., 2018; Callaini et al., 1997; Callaini et al., 1996; Duron and Weill, 2006). In addition, these late-developing CI-derived embryos also exhibit significant cellular defects including chromosome segregation errors, irregular spindles, displaced nuclei, and disorganized centrosomes (Callaini et al., 1997; Callaini et al., 1996; Lassy and Karr, 1996). In diplo-diploid species, late embryonic lethality is widely believed to be due to haploid development explained by the behavior of the paternal chromosomes during the first division (Bonneau et al., 2018; Callaini et al., 1997; Duron and Weill, 2006). While weak CI results in defective paternal chromosome segregation creating aneuploid nuclei that arrest in early embryonic development, strong CI results in complete failure of sister chromosome segregation and haploid nuclei bearing only the maternal chromosome complement (Bonneau et al., 2018; Callaini et al., 1997; Duron and Weill, 2006; Tram et al., 2006). Haploid embryos develop normally to the cellular blastoderm stage but then fail prior to hatching.

However, whether the numerous cellular defects observed in late-developing CI-derived embryos are also the result of first division errors has not been resolved. Here, we addressed this question by analyzing the timing, extent, and causes of mitotic defects observed specifically in late D. simulans embryos derived from CI crosses that seemingly bypass the first division defects and develop normally through early embryogenesis. Collectively, our results suggest that late embryonic defects are the result of a second CI-induced affect temporally distinct from first division errors. As discussed below, this suggests CI may be produced through either (1) a common acute mechanism that acts at both early and late development time points, or (2) separate and distinct early and late mechanisms that do not depend upon one another.

In accord with previous studies in D. simulans (Callaini et al., 1997; Callaini et al., 1996; Lassy and Karr, 1996), we found that there is a second late embryonic lethality associated with CI-derived embryos: between one-fourth and one-third of embryos die after cellularization but before hatching (Figure 1). However, while we found embryos derived from CI crosses were relatively normal during nuclear cycles 2–9 (Figure 2), previous reports (Callaini et al., 1996; Lassy and Karr, 1996) observed pre-blastoderm embryos with substantial mitotic defects. In these experiments, the percentage of abnormal CI-derived embryos fixed after a 6 hr age was similar to that of CI-derived embryos fixed immediately after collection, suggesting pre-blastoderm defects manifest from first division defects (Lassy and Karr, 1996). Therefore, embryos initially undergoing extensive first division defects may develop slowly through pre-blastoderm divisions if they are aged. As we fixed embryos directly after collecting with no aging time, a possible explanation for the low percentage of abnormal pre-blastoderm embryos we observed is that there was not enough time for embryos experiencing substantial first division segregation errors to develop through the pre-blastoderm stages. Instead, our fixing mostly captured the embryos that correspond to the previously reported percentage (~44%) of the CI-derived embryos that develop normally through the pre-blastoderm stage in spite of a later lethal phase (Lassy and Karr, 1996).

As the CI-derived embryos subsequently progressed through the cortical divisions (cycles 10–14), they begin to experience increasingly more severe defects. These late embryonic defects include lagging anaphase chromosomes and chromosome bridging, which directly result in nuclear fallout, and further chromosome bridging during gastrulation (Figures 3 and 4, Figure 4—figure supplement 1). The normal progression of embryos through cycles 2–9 suggests paternal chromosome segregation was not partially defective in the first division. This is because paternal chromosome bridging in the first division would produce aneuploid daughter nuclei bearing chromosome fragments lacking telomeres. The lack of telomeres would result in detectable breakage–fusion–bridge cycles and amplifications of the aneuploidy in subsequent divisions (McClintock, 1941; Titen and Golic, 2008), which we did not observe. Our sequencing analysis of cellularized embryos (Figure 5) confirms that late-stage CI embryos did not experience partial chromosome loss during the first division. Thus, the mitotic defects first observed in cortical syncytial divisions are unlikely a consequence of CI-induced segmental aneuploidy following the first nuclear cycle.

Consequently, our single embryo PCR and whole genome sequencing of cellularized embryos containing a paternally derived egfp transgene revealed late-stage CI embryos were either haploid or diploid (Figure 5). The percentage of diploid embryos closely corresponded to the percentage of embryos hatched, suggesting late embryonic lethality is associated with CI-induced haploidy in D. simulans, as previously reported (Callaini et al., 1997). Importantly, this experiment also demonstrated that the detection of paternally derived chromosomes in that late-stage CI embryos could be used to distinguish between embryos that had experienced first division defects (haploid = only maternal chromosomes, no paternal chromosomes) and embryos that had not experienced any first division defects (diploid = both maternal and paternal chromosomes). As discussed below, this allowed us to uncouple CI-induced late embryo defects from first division defects.

In spite of the strong association between haploidy and lethality, first division-induced haploidy in and of itself cannot explain the defects we observed in CI-derived blastoderm and gastrulating embryos. This is because (1) haploidy is not intrinsically harmful to mitotic divisions in Drosophila. For example, in some Drosophila mutations that induce haploidy, chromosome segregation occurs normally during cortical divisions (Tang et al., 2017). Additionally, meiosis II—essentially a mitotic division of a haploid nucleus—is highly accurate by necessity. Furthermore, (2) any downstream effects of haploidy—such as changes to zygotic gene copy number or loss of zygotic heterozygosity—cannot explain defects first detected in syncytial cortical divisions (cycles 10–13), which do not require zygotic transcription (Yuan et al., 2016). In contrast, the observed defects in CI-derived late embryos are more likely due to a second temporally deferred CI-induced defect.

In support of this hypothesis, our observation of increased chromosome segregation errors in diploid CI gastrulating embryos bearing paternally derived Y chromosomes establishes that the defects observed in late-stage CI embryos are not limited to haploids (Figure 6). Instead, defects are present in diploid late-stage embryos. Significantly, as discussed above for the paternally derived egfp transgene, detection of the Y chromosome by FISH allowed us to select late-stage diploid embryos that had ‘escaped’ first division defects and instead continued development with both paternal and maternal chromosome complements. Therefore, the significant increase in mitotic errors observed in diploid CI-derived embryos relative to wild-type-derived embryos demonstrates the existence of a second, CI-induced defect, temporally and possibly mechanistically distinct from the first division defect (Figure 7A, B). Significantly, maternally supplied Wolbachia independently rescues this later second defect as well (Figure 7C).

Figure 7

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Interestingly, we also observed several non-Y-bearing gastrulating embryos from CI crosses that had extensive chromosome segregation errors beyond what we had observed for the diploid Y-bearing gastrulating embryos (Figure 6—figure supplement 2). Non-Y-bearing embryos may either be diploid (XX) or haploid (XØ). If these embryos were haploid, this observation would suggest that CI could affect both the maternal chromosomes and paternal chromosomes.

One intriguing aspect of the second CI-induced defect is that the embryos progress normally through the early mitotic cycles and then begin to exhibit mitotic defects in the blastoderm stage. The explanation is likely a consequence of the dramatic structural and regulator cell cycle modifications that occur when the dividing nuclei arrive at the cortex (Farrell and O’Farrell, 2014). These include heterochromatin formation, initiation of late origins of replication, slowing of DNA replication, activation of zygotic transcription, and metaphase furrow formation (Farrell and O’Farrell, 2014; Li et al., 2014; Riggs et al., 2003; Seller et al., 2019; Seller and O’Farrell, 2018). The phenotype of numerous maternal-effect mutations that either rely on or disrupt these processes is strikingly similar to the defects observed in CI embryos: normal early pre-cortical divisions followed by extensive mitotic errors and nuclear fallout during the cortical blastoderm divisions (Sullivan and Theurkauf, 1995). For example, because of the slowing of DNA replication during the cortical divisions, activation of the S-phase checkpoint is specifically required during this stage. Maternal-effect mutants that disrupt this checkpoint progress normally through the early divisions but exhibit anaphase bridging and nuclear fallout during the late cortical blastoderm divisions as a result of entering metaphase with incompletely replicated chromosomes (Fogarty et al., 1997; Fogarty et al., 1994). Given the similarity of this phenotype, both in timing and chromosome dynamics, CI-induced late division defects may be due to improper or abnormally slow chromosome replication. Additionally, defects in other events specific to the cortical blastoderm cycles, may also contribute directly or indirectly to CI-induced defects. For example, studies of hybrid incompatibilities between D. simulans and D. melanogaster show that heterochromatin establishment may be particularly sensitive, and its disruption can result in defects strikingly similar to the late CI defects (Ferree and Barbash, 2009). Other important processes, such as those involved in DNA integrity, protein turnover, and cell cycle timing, may be also involved (Momtaz et al., 2020).

In considering the mechanism by which paternal Wolbachia may induce these defects, the observation that CI-derived blastoderm embryos progress normally through pre-cortical divisions must be noted. One potential explanation is that the chromosomes in CI-derived embryos could be epigenetically marked by Wolbachia in the paternal germline. This mark would then persist through the pre-cortical divisions and become disruptive during blastoderm divisions. Interestingly, Wolbachia infection results in altered DNA methylation levels in certain wasps, mosquitos, leafhoppers, and Drosophila (LePage et al., 2014; Negri et al., 2009; Wu et al., 2020; Ye et al., 2013). Should Wolbachia in the male germline similarly change the low naturally occurring methylation levels in D. simulans (Deshmukh et al., 2018), the altered mark may become disruptive in blastoderm divisions, potentially by distorting heterochromatin establishment. However, DNA methylation does not appear to contribute to CI levels (LePage et al., 2014).

An alternative explanation for the specificity of the late blastoderm defects comes from studies into hybrid dysgenesis in D. melanogaster in which unregulated mobilization of transposable elements results in a spectrum of genetic and developmental defects in the germlines of dysgenic progeny (Kidwell et al., 1977). Transposition in progeny can be suppressed when maternally supplied small RNAs mediate silencing of the transposable element (Czech and Hannon, 2016). This silencing is associated with increased H3K9 methylation, increased heterochromatin levels, and altered splicing (Le Thomas et al., 2013; Sienski et al., 2012; Teixeira et al., 2017). Given small RNAs can affect chromosomes in trans (Hermant et al., 2015), CI may induce a similar small RNA pathway that could epigenetically alter both paternal and maternal chromosomes prior to the first division. As the blastoderm divisions do not require zygotic transcription (Yuan et al., 2016), it is unlikely an epigenetic alteration, if occurring, would cause defects via disrupted transcription. Instead, as discussed above, an epigenetic change may disrupt key aspects of the mid-blastula transition, which in turn could result in the observed errors.

Insight into the molecular mechanism of CI came with the discovery of the Wolbachia-encoded Cifs that play a key role in CI and rescue (Beckmann et al., 2017; LePage et al., 2017). A combination of molecular, genetic, and biochemical studies provided compelling evidence that the Wolbachia encoded genes, CidB and CidA, act as a paternally supplied toxin and maternally supplied anti-toxin, respectively (Beckmann et al., 2017; Horard et al., 2022; Wang et al., 2022). However, a toxin/anti-toxin model for CI does not easily explain the cortical blastoderm defects occurring after many rounds of normal mitotic cycles. This is because a paternally supplied toxin is expected to be diluted with every round of division, and therefore its induced defects would decrease over time. Similarly, a second set of CI/rescue elements, CinA and CinB, is also proposed to act in a toxin/anti-toxin manner (Chen et al., 2019; Sun et al., 2022). An alternative possibility is that Cifs may epigenetically modify paternal and maternal chromosomes to mediate CI and rescue (Kaur et al., 2022).

How and if these proteins also contribute to CI-induced late-embryo defects remains to be determined. It is possible that early and late defects are caused by common acute mechanisms involving the known Cifs. This may be due to an induced chromosomal change that produces defects at different times given natural variation in developmental processes among a population of embryos. In contrast, chromosome segregation errors in diploid embryos that have progressed normally through the first division may suggest minimal Cif activity and an additional set of Wolbachia genes that induce late-embryo defects. Unlike the first division errors, CI-induced mitotic defects in late embryos do not appear to result from abnormal condensation, alignment, or timing of metaphase exit (Figure 4). Instead, the observed chromosome bridging is strikingly similar to embryos exposed to the DNA replication inhibitor aphidicolin (Farrell et al., 2012; Fasulo et al., 2012), suggesting CI-derived blastoderm embryos may be entering anaphase with incompletely replicated chromosomes. These differences could suggest a separate proximate cause for early and late defects, or provide additional insight into Cif-induced defects. Thus, any model of CI and rescue, be it toxin/anti-toxin, lock-key, titration, or timing, must account for the fact that some effects of Wolbachia on the sperm are not realized until hours and many cell cycles later when the embryos progress through the late blastoderm divisions and the mid-blastula transition.

Sequencing data have been deposited in the Sequence Read Archive (BioProject PRJNA848235). Figure 5—source data 1 contains the raw unedited gel used to generate Figure 5B as well as Figure 5 prepared with the raw gel. Figure 5—source data 2 contains numerical source data to generate Figure 5E. All reagents used are available upon request.

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Author details

1. Brandt Warecki

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

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

   Contributed equally with

   Simon William Abraham Titen

   For correspondence

   bwarecki@ucsc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-8025-6246

2. Simon William Abraham Titen

   1. Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States
   2. Department of Biology and Chemistry, California State University Monterey Bay, Seaside, United States

   Contribution

   Conceptualization, Formal analysis, Validation, Investigation, Methodology, Writing – review and editing

   Contributed equally with

   Brandt Warecki

   Competing interests

   No competing interests declared

3. Mohammad Shahriyar Alam

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

   Conceptualization, Formal analysis, Investigation, Writing – original draft, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2943-8084

4. Giovanni Vega

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

   Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

5. Nassim Lemseffer

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

6. Karen Hug

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

   Formal analysis, Investigation

   Competing interests

   No competing interests declared

7. Jonathan S Minden

   Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, United States

   Contribution

   Methodology

   Competing interests

   No competing interests declared

8. William Sullivan

   Department of Molecular, Cell, and Developmental Biology, University of California, Santa Cruz, Santa Cruz, United States

   Contribution

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

   For correspondence

   wtsulliv@ucsc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-1756-4174

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