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Temporal and spatial expression of Hoxa2 gene in the developing mouse palate and the effects of valproic acid on Hoxa2 expression during murine palatogenesis

dc.contributor.advisorNazarali, A.en_US
dc.contributor.committeeMemberLehotay, D.en_US
dc.contributor.committeeMemberBlakley, B. R.en_US
dc.contributor.committeeMemberTuchek, J.en_US
dc.contributor.committeeMemberKulyk, W.M.en_US
dc.creatorZhang, Weien_US 2003en_US
dc.description.abstractHoxa2, a second arch selector gene, when deleted results in many cranial abnormalities including a cleft plate. The occurrence of cleft plate in the Hoxa2-/- mice is reported to be due to a secondary effect and Hoxa2 gene has been assumed not to be present in the palate. However, Hoxa2 gene and protein, have recently been demonstrated to be expressed in the developing palate. This finding was extended and a detailed temporal and spatial pattern of expression of Hoxa2 was identified in the developing murine palate. Hoxa2 protein expression is detected in palatal epithelium as early as embryonic stage 12 (E12). From E12 to E13.5, Hoxa2 expression extends to the mesenchyme, where intensity of expression is enhanced. At E13-13.5, Hoxa2 protein and mRNA expression is the highest in the outer lateral half of the elongating palatal shelves. At E14-14.5 when the palatal shelves elevate above the tongue to a horizontal position, Hoxa2 expression is down regulated in the mesenchyme, Hoxa2 continues to be expressed in the palatal epithelium and the medial edge of the epithelium at this stage. The temporal and spatial pattern of Hoxa2 expression in the developing palate is in concordance with the cytoarchitectural changes occurring in the growing palate. In vitro whole organ palatal cultures show that palates from Hoxa2-/- mice exhibit a much lower fusion rate (44.4%) compared to their heterozygous or wild type counterparts (78.7%, 90% respectively). In the wild-type palate organ culture group exposed to valproic acid (VPA), a clinically used anticonvulsant drug and a known teratogen that can induce a cleft palate and other abnormalities in mice and humans, Hoxa2 mRNA is downregulated within the palatal shelf as determined by RT-PCR in a dose dependent manner. These results provide evidence that cleft palate induced in Hoxa2-/- mice is not only secondary to an altered positioning of the tongue but is also due to an absence of Hoxa2 gene expression which results in delayed palatal development. The percentage of cleft palate calculated as a result of delayed palatal development is 45.6% in Hoxa2-/- mice, whereas the percentage of cleft palate secondary to the abnormal position of the tongue accounts for approximately a third in these mice. However, both of the factors, a delay in palatal growth and an abnormal tongue position act combinatorially to give the reported incidence of 82% cleft palate in the Hoxa2 knockout mice. These results demonstrate a direct role for Hoxa2 in palatogenesis. In addition, the ability of VPA to alter the Hoxa2 expression in the palate during palatogenesis suggests one possible mechanism of VPA induced cleft palate.en_US
dc.titleTemporal and spatial expression of Hoxa2 gene in the developing mouse palate and the effects of valproic acid on Hoxa2 expression during murine palatogenesisen_US
dc.type.materialtexten_US of Saskatchewanen_US of Science (M.Sc.)en_US


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