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Vax1 Plays an Indirect Role in the Etiology of Murine Cleft Palate

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)1555-1562
JournalJournal of Dental Research
Issue number13
Early online date3 Aug 2017
Publication statusPublished - 1 Dec 2017


  • Vax1 Plays an Indirect_GEOGHEGAN_Publishedonline3August2017_GREEN AAM

    Vax1_Plays_an_Indirect_GEOGHEGAN_Publishedonline3August2017_GREEN_AAM.pdf, 1.57 MB, application/pdf


    Accepted author manuscript


    This is the peer-reviewed accepted manuscript of a paper published in Journal of Dental Research (Sage, 2017).
    F. Geoghegan, , G.M. Xavier, , A.A. Birjandi, M. Seppala, , M.T. Cobourne, Journal of Dental Research Vol 96, Issue 13, pp. 1555 - 1562

    © International & American Associations for Dental Research 2017.
    The final published version is available at

King's Authors


Cleft lip with or without palate (CLP) and isolated cleft palate (CP) are common human developmental malformations with a complex etiology that reflects a failure of normal facial development. VAX1 encodes a homeobox-containing transcription factor identified as a candidate gene for CLP in human populations, with targeted deletion in mice associated with multiple anomalies, including disruption of the visual apparatus and basal forebrain, lobar holoprosencephaly, and CP. We have investigated Vax1 function during murine palatogenesis but found no evidence for a direct role in this process. Vax1 is not expressed in the developing palate and mutant palatal shelves elevate above the tongue, demonstrating morphology and proliferation indices indistinguishable from wild type. However, mutant mice did have a large midline cavity originating from the embryonic forebrain situated beneath the floor of the hypothalamus and extending through the nasal cavity to expand this region and prevent approximation of the palatal shelves. Interestingly, despite strong expression of Vax1 in ectoderm of the medial nasal processes, the upper lip remained intact in mutant mice. We found further evidence of disrupted craniofacial morphology in Vax1 mutants, including truncation of the midface associated with reduced cell proliferation in forebrain neuroectoderm and frontonasal mesenchyme. Sonic hedgehog (Shh) signal transduction was downregulated in the mutant forebrain, consistent with a role for Vax1 in mediating transduction of this pathway. However, Shh was also reduced in this region, suggestive of a Shh-Vax1 feedback loop during early development of the forebrain and a likely mechanism for the underlying lobar holoprosencephaly. Despite significant associations between VAX1 and human forms of CLP, we find no evidence of a direct role for this transcription factor in development of this region in a mutant mouse model.

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