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bioRxiv · 10.1101/2023.02.15.528754

Divergent phenotypes in germline versus conditional mutant mouse models of Sifrim-Hitz- Weiss Syndrome

Larrigan, S.·Joshi, S.·Mattar, P.
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Abstract

Chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), however, their functions during brain development are not fully understood. Here, we focused on Sifrim-Hitz-Weiss Syndrome (SIHIWES) - a brain overgrowth/intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain - either in the germline, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited little change in cortical size and cellular composition, and had only subtle behavioral phenotypes. Telencephalon-specific conditional knockouts had marked reductions in cortical growth, reduced numbers of upper-layer neurons, and exhibited alterations in anxiety and repetitive behaviors. Despite the fact that germline heterozygotes exhibited comparable growth defects, they were unaffected in these behaviors, but instead exhibited female-specific alterations in learning and memory. These data reveal unexpected phenotypic divergence arising from differences in the spatiotemporal deployment of loss-of-function manipulations, underscoring the importance of context in chromatin remodeller function during neurodevelopment. Graphical Abstract. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=90 SRC="FIGDIR/small/528754v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@ffdb72org.highwire.dtl.DTLVardef@1a0231corg.highwire.dtl.DTLVardef@613242org.highwire.dtl.DTLVardef@12ac3ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Larrigan, S., Joshi, S., Mattar, P.. 2023-02-16. Divergent phenotypes in germline versus conditional mutant mouse models of Sifrim-Hitz- Weiss Syndrome. https://doi.org/10.1101/2023.02.15.528754

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