Loss of SPECC1L in cranial neural crest cells results in increased hedgehog signaling and frontonasal dysplasia

TL;DR

Deleting the SPECC1L gene in cranial neural crest cells in mice causes facial abnormalities similar to those seen in a human genetic syndrome.

Contribution

A new mouse model shows that SPECC1L loss in neural crest cells leads to craniofacial defects via increased Hedgehog signaling.

Findings

SPECC1L deletion in cranial neural crest cells causes shortened skulls and nasal defects in mice.

Loss of SPECC1L results in shortened primary cilia and increased Hedgehog signaling activity in cranial mesenchyme.

Early facial defects in Specc1lΔCNCC mice suggest developmental origins of adult craniofacial abnormalities.

Abstract

SPECC1L encodes a cytoskeletal scaffolding protein that interacts with filamentous actin, microtubules, and cell junctional components. In humans, autosomal dominant mutations in SPECC1L cause a syndrome characterized by craniofrontonasal anomalies including broad nasal bridge, ocular hypertelorism, prominent forehead, and cleft lip/palate. Complete loss of SPECC1L in mice on a homogeneous genetic background results in perinatal lethality, accompanied by subtle cranial differences and incompletely penetrant cleft palate. This lethality limits postnatal analysis of craniofacial development. Because cranial neural crest cells (CNCCs) contribute extensively to the formation of anterior craniofacial structures, we investigated whether disruption of SPECC1L in CNCCs contributes to the craniofrontonasal phenotypes observed in SPECC1L-related syndrome. We generated a Specc1l-floxed allele and crossed it with the Wnt1-Cre2 deleter strain, which drives Cre recombinase expression in the dorsal neuroectoderm and NCCs. Most homozygous Specc1l

ΔCNCC
mutants survived postnatally and exhibited hallmark features of the human SPECC1L-related syndrome, including shortened skulls, reduced frontal bone area, nasal defects, and midface hypoplasia. The cranial mesenchyme of Specc1l

ΔCNCC
mice displayed shortened primary cilia and increased Hedgehog (Hh) signaling activity at E13.5, as evidenced by enhanced GLI1 immunostaining. These defects were also observed early in E9.5 facial prominences, indicating that they may drive the adult phenotype. Collectively, Specc1l

ΔCNCC
mice provide a novel model for investigating the roles of CNCCs, primary cilia, and Hh signaling in frontonasal prominence and midfacial development.

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