Analysis of Gbx genes during neural development
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[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] The understanding of how transcription factors regulate neural patterning in the anterior hindbrain, and how the assembly of specific neuronal circuits controlling motor behavior in the developing spinal cord are important concerns in the field of developmental biology. In this dissertation we used two animal models, mouse and zebrafish, to study how gastrulation-brain homeobox (Gbx) class transcription factors (Gbx1 and Gbx2), affect the formation of sensorimotor circuits in mice and the development of anterior hindbrain in zebrafish. We use gene inactivation to study the role of Gbx1 and gbx2 during mouse and zebrafish embryogenesis. Gbx1 mutant (Gbx1-/-) mice develop a severe defect in motor coordination specifically affecting hindlimb gait. Loss of Gbx1 also resulted in an aberrant projection of the Ia proprioceptive sensory fiber in the ventral horn of the developing spinal cord. In addition, we show that Gbx1-/- embryos exhibit a reduction of Islet 1+ (ISL1) ventral motor neurons beginning at E14.5. In a parallel study, we investigated the role of gbx2 in the development of the anterior hindbrain in zebrafish embryos (Burroughs-Garcia et al., 2011). Gbx2 is widely known in mice and other vertebrates for it role positioning the mid hindbrain boundary. Despite many studies in mice showing the need of Gbx2 for normal hindbrain development, only few studies have focused on this role for Gbx2 in other vertebrates. Since the expression of Gbx2 in anterior hindbrain is conserved among vertebrate, we investigated whether the role of Gbx2 is functionally conserved during anterior hindbrain development in zebrafish. Loss-of-function studies using antisense morpholino show that gbx2 mutant embryos exhibit similar developmental defects as seen in hypomorphic mice (Waters and Lewandoski, 2006). We showed that deletion of gbx2 results in a truncation of the anterior hindbrain region between rhombomere (r)1 and r3 (Burroughs-Garcia et al., 2011). Furthermore there is an abnormal clustering of nV cell bodies arising from r2 and r3. These phenotypes can be rescued by injecting mouse Gbx2 mRNA (Buckley et al., 2013). This dissertation provides the first functional analysis of Gbx1 during mouse embryonic development. Additionally, our results provide evidence that gbx2/Gbx2 has shared an evolutionarily conserved role during the development of the anterior hindbrain in zebrafish embryos.
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