Abstract
Neural crest cells (NCC) give rise to much of the tissue that forms the vertebrate head and face, including cartilage and bone, cranial ganglia and teeth. In this study we show that conditional expression of a dominant-negative (DN) form of Rho kinase (Rock) in mouse NCC results in severe hypoplasia of the frontonasal processes and first pharyngeal arch, ultimately resulting in reduction of the maxilla and nasal bones and severe craniofacial clefting affecting the nose, palate and lip. These defects resemble frontonasal dysplasia in humans. Disruption of the actin cytoskeleton, which leads to abnormalities in cell-matrix attachment, is seen in the RockDN;Wnt1-cre mutant embryos. This leads to elevated cell death, resulting in NCC deficiency and hypoplastic NCC-derived craniofacial structures. Rock is thus essential for survival of NCC that form the craniofacial region. We propose that reduced NCC numbers in the frontonasal processes and first pharyngeal arch, resulting from exacerbated cell death, may be the common mechanism underlying frontonasal dysplasia.
Highlights
The vertebrate face is largely formed from neural crest-derived mesenchyme, covered in ectoderm, with a small endodermal contribution
The Rock dominant-negative (RockDN) protein RB/PH (TT) [12,14] is unable to bind to Rho and blocks Rock function [15]
To assess the efficiency of cre recombination we evaluated the levels of the CAT gene cassette transcripts in pharyngeal arches 1 and 2 of embryonic heads taken from RockDN+;Wnt1-cre+ mutants and RockDN+;Wnt1-cre2 controls at E11.5, as this tissue was rich in Neural crest cells (NCC) (Figure S1 C,D)
Summary
The vertebrate face is largely formed from neural crest-derived mesenchyme, covered in ectoderm, with a small endodermal contribution (reviewed in [1]). The surface ectoderm and pharyngeal endoderm have important signalling roles in the patterning of the forming craniofacial region, it is the cranial neural crest cells (NCC) that form most of the bone and cartilage within the head, the teeth and the cranial ganglia. Three paired prominences, derived from the first pharyngeal arch, form the lateral regions of the mid and lower face, associated with the maxilla, the mandible and the secondary palate [1]. In order for these initially featureless prominences to give rise to their complex derivatives, processes of growth, expansion and fusion have to be orchestrated. Mouse and chick, have highlighted the importance of specific signalling cascades, including the sonic hedgehog, fibroblast growth factor and bone morphogenetic protein pathways, in the development of the craniofacial region [1,2]
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