| First Author | Larrigan S | Year | 2023 |
| Journal | Hum Mol Genet | Volume | 32 |
| Issue | 24 | Pages | 3361-3373 |
| PubMed ID | 37738575 | Mgi Jnum | J:343553 |
| Mgi Id | MGI:7565973 | Doi | 10.1093/hmg/ddad157 |
| Citation | Larrigan S, et al. (2023) Divergent phenotypes in constitutive versus conditional mutant mouse models of Sifrim-Hitz-Weiss syndrome. Hum Mol Genet 32(24):3361-3373 |
| abstractText | 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)-an intellectual disability disorder caused by mutations in the CHD4 chromodomain helicase gene. We utilized mouse genetics to excise the Chd4 ATPase/helicase domain-either constitutively, or conditionally in the developing telencephalon. Conditional heterozygotes exhibited no 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 whole-body 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. |
