Hedgehog receptor function during craniofacial development

Abstract

The Hedgehog signalling pathway plays a fundamental role in orchestrating normal craniofacial development in vertebrates. In particular, Sonic hedgehog (Shh) is produced in three key domains during the early formation of the head; neuroectoderm of the ventral forebrain, facial ectoderm and the pharyngeal endoderm; with signal transduction evident in both ectodermal and mesenchymal tissue compartments. Shh signalling from the prechordal plate and ventral midline of the diencephalon is required for appropriate division of the eyefield and forebrain, with mutation in a number of pathway components associated with Holoprosencephaly, a clinically heterogeneous developmental defect characterized by a failure of the early forebrain vesicle to divide into distinct halves. In addition, signalling from the pharyngeal endoderm and facial ectoderm plays an essential role during development of the face, influencing cranial neural crest cells that migrate into the early facial processes. In recent years, the complexity of Shh signalling has been highlighted by the identification of multiple novel proteins that are involved in regulating both the release and reception of this protein. Here, we review the contributions of Shh signalling during early craniofacial development, focusing on Hedgehog receptor function and describing the consequences of disruption for inherited anomalies of this region in both mouse models and human populations.

Sonic Hedgehog regulation of Foxf2 promotes cranial neural crest mesenchyme proliferation and is disrupted in cleft lip morphogenesis

“…Specifically, secretion of SHH ligand from the ectoderm activates pathway activity in the adjacent cranial neural crest-derived mesenchyme (Marcucio et al, 2005;Hu and Marcucio, 2009;Hu et al, 2015;Xavier et al, 2016). Demonstrating clinical relevance, we have shown that transient in utero exposure to the Shh pathway inhibitor cyclopamine causes lateral clefts of the lip that typically extend into the primary and secondary palate, and that this model recapitulates human non-syndromic cleft lip with or without cleft palate (CL/P) (Lipinski et al, 2008b(Lipinski et al, , 2010(Lipinski et al, , 2014.…”

Functional analysis of the zebrafish ortholog of HMGCS1 reveals independent functions for cholesterol and isoprenoids in craniofacial development

“…Shh signaling is an important component of proper craniofacial development [13,29]. Furthermore, Shh signaling is mediated by post translational cholesterol modifications [30] and mutations in the proteins that facilitate these modifications have been associated with craniofacial abnormalities [31–33].…”

“…Mutations in either the murine or telost Disp1 genes result in craniofacial abnormalities [31,33]. Moreover, human mutations in the Shh pathway cause overlapping phenotypes when compared with mutations that interfere with the cholesterol synthesis pathway [29,52]. In vitro experiments also suggest that deficiencies in the cholesterol synthesis pathway reduce Shh signaling by interfering with smoothened activation, but very few studies have linked these two pathways in vivo [11].…”

Emerging Roles of Sonic Hedgehog in Adult Neurological Diseases: Neurogenesis and Beyond

“…In addition to the developmental specification of the cell fate, Shh signaling plays crucial roles in early patterning of the embryonic brain, notably to regulate polarity of the central nervous system (CNS) [6] as well as to guide the ventral patterning in the spinal cord [7]. These features are important for craniofacial development because disruption of Shh signaling pathway may cause craniofacial neural crest cell death, thereby resulting in craniofacial anomalies in both vertebrate models and human populations [8,9]. During early stages of head formation, Shh is produced in three key domains, namely neuroectoderm of the ventral forebrain, facial ectoderm, and the pharyngeal endoderm [8,9].…”

“…These features are important for craniofacial development because disruption of Shh signaling pathway may cause craniofacial neural crest cell death, thereby resulting in craniofacial anomalies in both vertebrate models and human populations [8,9]. During early stages of head formation, Shh is produced in three key domains, namely neuroectoderm of the ventral forebrain, facial ectoderm, and the pharyngeal endoderm [8,9]. Shh signaling is critical for orchestrating the fundamental organization of the craniofacial region [10,11].…”