Genetic interaction of <i>Specc1l</i> and <i>Thm1</i> reveals cytoskeletal - ciliary crosstalk

Cilium formation and actin cytoskeleton dynamics are interconnected, with evidence showing that elevated filamentous actin (F-actin) negatively regulates primary cilia length. Loss of the cytoskeletal protein SPECC1L, which itself does not localize to cilia, leads to increased F-actin and shortened cilia. Depolymerizing F-actin in <i>Specc1l</i> mutant cells restored cilia lengths, substantiating this inverse relationship. In cells harboring a <i>Specc1l</i> allele lacking only the coiled-coil domain 2, intracellular regions with both elevated and reduced F-actin were observed together with cilia shortening. Notably, F-actin was decreased at the ciliary base, suggesting that a different F-actin subpopulation contributes to the inverse relationship. We also identified a genetic interaction between <i>Specc1l</i> and <i>Thm1</i>, which encodes an intraflagellar transport-A (IFT-A) protein. Double or compound heterozygotes for <i>Specc1l</i> and <i>Thm1</i> exhibited a higher penetrance of cleft palate compared to <i>Specc1l</i> heterozygotes alone. Together, these findings reveal a role for SPECC1L in cytoskeletal regulation of ciliogenesis affecting palate development.