Abstract
There are 8 different human syndromes caused by mutations in the cholesterol synthesis pathway. A subset of these disorders such as Smith-Lemli-Opitz disorder, are associated with facial dysmorphia. However, the molecular and cellular mechanisms underlying such facial deficits are not fully understood, primarily because of the diverse functions associated with the cholesterol synthesis pathway. Recent evidence has demonstrated that mutation of the zebrafish ortholog of HMGCR results in orofacial clefts. Here we sought to expand upon these data, by deciphering the cholesterol dependent functions of the cholesterol synthesis pathway from the cholesterol independent functions. Moreover, we utilized loss of function analysis and pharmacological inhibition to determine the extent of sonic hedgehog (Shh) signaling in animals with aberrant cholesterol and/or isoprenoid synthesis. Our analysis confirmed that mutation of hmgcs1, which encodes the first enzyme in the cholesterol synthesis pathway, results in craniofacial abnormalities via defects in cranial neural crest cell differentiation. Furthermore targeted pharmacological inhibition of the cholesterol synthesis pathway revealed a novel function for isoprenoid synthesis during vertebrate craniofacial development. Mutation of hmgcs1 had no effect on Shh signaling at 2 and 3 days post fertilization (dpf), but did result in a decrease in the expression of gli1, a known Shh target gene, at 4 dpf, after morphological deficits in craniofacial development and chondrocyte differentiation were observed in hmgcs1 mutants. These data raise the possibility that deficiencies in cholesterol modulate chondrocyte differentiation by a combination of Shh independent and Shh dependent mechanisms. Moreover, our results describe a novel function for isoprenoids in facial development and collectively suggest that cholesterol regulates craniofacial development through versatile mechanisms.
Highlights
Craniofacial malformations are a group of heterogeneous disorders that describe developmental defects of the head and facial bones
Our data confirm that deficiencies in cholesterol biosynthesis interfere with vertebrate craniofacial development, but in addition, we demonstrate a novel function for isoprenoids in neural crest cells (NCC) differentiation and facial development
Mutation of the zebrafish hmgcrb gene is associated with orofacial clefts [5] and we hypothesized that mutations in hmgcs1 result in craniofacial defects
Summary
Craniofacial malformations are a group of heterogeneous disorders that describe developmental defects of the head and facial bones. The most common forms of craniofacial abnormalities include cleft lip/palate, craniosynostosis, and facial dysostoses. The prevalence of such disorders encompasses over 1/3 of all congenital malformations [1]. The cholesterol synthesis pathway produces two separate, but important molecules: cholesterol, a common membrane component, and isoprenoids, molecules important for protein prenylation and cell signaling. The first step of the pathway is mediated by HMGCS1, the gene that encodes HMG-CoA synthase, which converts acetyl CoA and acetoacetyl-CoA into 3-hydroxy-3-methylglutaryl CoA (HMG-CoA). HMG-CoA is reduced by HMG-CoA reductase (encoded by HMGCR) into mevalonate in the rate limiting step of the reaction. The subsequent production of farnesyl pyrophosphate represents a branch point in the pathway, serving as a substrate for either cholesterol or isoprenoid synthesis
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