SPECC1L: A Novel Cytoskeletal Regulator of Epithelial Organization in Craniofacial Morphogenesis

Abstract

Craniofacial anomalies are extremely common among birth defects, with clefts of the lip and palate affecting approximately 1/700 live‐births. While many contributory genes have been identified, a large proportion of the genetic component of this complex disease is unknown. Thus, there is a continued need to identify additional genes and to understand underlying pathogenetic mechanisms. We first identified heterozygous SPECC1L mutations in two patients with atypical facial clefts and cleft palate. New heterozygous missense SPECC1L mutations have been identified in two autosomal dominant Opitz G/BBB syndrome families with hypertelorism and cleft palate, and in two patients with Teebi hypertelorism syndrome, underscoring the importance of SPECC1L in craniofacial development. To understand the role of SPECC1L, we have generated several mouse models with null and hypomorphic (truncation, in‐frame deletion, missense) mutations. Mutants for these alleles manifest a range of structural malformations, including exencephaly, cleft palate and ventral body wall defects. The homozygous null mutants die by embryonic day 9.5 (E9.5) with an open neural tube and failure of cranial neural crest cells to delaminate from the neuroectoderm. We have shown that the latter is due to increased expression of adherens junction markers in the neuroectoderm and reduced PI3K‐AKT signaling. Homozygous mutants for a hypomorphic allele that results in SPECC1L truncation die perinatally and show midline subepidermal blebbing with no cleft palate. Specc1lnull/hypo compound mutants with moderate SPECC1L deficiency show palate elevation defects at E14.5, which resolve within one embryonic day such that only a few mutants are born with cleft palate. However, these compound mutants show abnormal organization of the oral periderm of palatal shelves and occasional oral adhesions at E13.5. Consistent with these periderm anomalies, SPECC1L expression in the palate requires IRF6, thus making it a novel member of the IRF6/GRHL3 pathway in periderm development. Lastly, homozygous mouse mutants carrying human Opitz G/BBB patient mutation (T397P) show highly penetrant cleft palate, indicating a gain‐of‐function that specifically affects palatogenesis. Given the broad phenotypic spectrum of Specc1l allelic series mutants, our studies indicate that SPECC1L regulates epithelial organization at various stages and in multiple tissues throughout embryonic development.Support or Funding InformationThis research is supported by NIH/NIDCR R01DE026172.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.