The role of Vax1 in craniofacial development

Student thesis: Doctoral ThesisDoctor of Philosophy


Holoprosencephaly (HPE) is a clinically heterogeneous developmental anomaly affecting the CNS and face, in which the embryonic forebrain fails to divide into distinct halves. Numerous genetic loci and environmental factors are implicated in HPE, but mutation in the sonic hedgehog (Shh) gene is an established cause in both humans and mice. Vax (ventral anterior homeobox) genes are a family of homeobox-containing genes which have been identified in mice, humans, Xenopus, chicken and zebrafish. They are transcription factors which are induced by Shh and ventralize the forebrain. In humans, it has been shown that a VAX1 mutation is associated with microphthalmia, agenesis of the corpus callosum, and orofacial clefting.
Skeletal and histological analysis of Vax1-/- mice revealed a series of craniofacial defects predominently affecting the neurocranial and facial midlines as well as the visual and olfactory systems. These included anomalies of the ventral forebrain, a single maxillary incisor, premaxillary hypoplasia, cleft palate and the presence of an ectopic second pituitary gland. During early facial development, Vax1 was expressed in the developing ventral forebrain and facial structures in adjacent and partially overlapping areas of expression to Shh and in a broadly reciprocal manner to its' transcriptional target Ptch1. In the absence of Vax1 function, there was an overall reduction in the size of craniofacial regions, in particular of the developing forebrain. Moreover, mutant mice did have a midline cavity originating from the embryonic forebrain and extending through the nasal cavity to expand this region and prevent approximation of the palatal shelves. This was combined with a decrease in cellular proliferation in this region and reduced Shh signaling activity. This phenotypic and molecular analysis was strongly indicative of the role of Vax1 downstream of Shh during craniofacial development.
Vax1-/- mice also demonstrate lobar HPE. Shh expression was reduced in both Gas1-/- and Vax1-/- mice, both modifiers of HPE. The craniofacial phenotype of Gas1 ;Vax1 compound mutant mice displayed a more severe defect of the facial midline thus demonstrating the combinatorial role of modifying genes in the wide spectrum of phenotypic variablility in Shh mediated HPE.
Date of Award2018
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorMartyn Cobourne (Supervisor) & Karen Liu (Supervisor)

Cite this