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dc.contributor.advisorSaadi, Irfan
dc.contributor.authorWilson, Nathan Ray
dc.description.abstractOrofacial clefts are frequent congenital malformations, which can result from reduced contribution of cranial neural crest cells (CNCCs) to the developing cranium. Upon delamination from embryonic neural folds, CNCCs migrate to pharyngeal arches, which give rise to mid-facial structures. Previously, mutations in the cytoskeletal gene SPECC1L were implicated in rare, severe atypical facial clefting. Overexpression of a patient isolated SPECC1L mutation showed disrupted association with acetylated microtubules. We show a similar disruption upon overexpression of SPECC1L variants isolated from patients with less severe syndromic cleft lip and palate. Severe Specc1l deficiency in homozygous mouse mutants is embryonic lethal, showing a reduction in pan-AKT levels and arrested CNCC delamination from the neural folds. Staining of adherens junction (AJ) proteins is increased in mutant neural folds, consistent with impaired CNCC delamination, a process requiring AJ dissolution. In vitro, AJ changes induced by SPECC1L-kd are rescued by activating PI3K-AKT signaling. We also looked at cell migration properties of SPECC1L-deficient cells in vitro. Collective cell migration is a cooperative process fundamental to embryonic development. Wound-repair assays using primary mouse embryonic palatal mesenchyme (MEPM), derived from CNCCs, with moderate Specc1l deficiency show impaired collective migration with reduced correlation lengths. These data indicate SPECC1L as a novel modulator of AJs and PI3K-AKT signaling in CNCC delamination and migration of CNCC-derived cells in craniofacial development.
dc.format.extent176 pages
dc.publisherUniversity of Kansas
dc.rightsCopyright held by the author.
dc.subjectCellular biology
dc.subjectAdherens junctions
dc.subjectcraniofacial development
dc.subjectfacial clefting
dc.subjectneural crest
dc.titleCharacterization of SPECC1L function in cell adhesion and migration in craniofacial morphogenesis
dc.contributor.cmtememberCzirok, Andras
dc.contributor.cmtememberKinsey, William
dc.contributor.cmtememberTrainor, Paul
dc.contributor.cmtememberTran, Pamela
dc.contributor.cmtememberWang, Jinxi
dc.thesis.degreeDisciplineAnatomy & Cell Biology

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