Functional analysis of Hoxa5: analysis of structural, behavioral, and molecular effects of Hoxa5 overexpression in transgenic line Hoxa5SV2
The purpose of this research was to provide new information on the role of a murine homeobox gene, Hoxa5, in the development of the central and peripheral nervous systems. Although Hoxa5 is expressed in the brachial spinal cord and enteric neuroblasts during development, no neural phenotype has yet been observed in the Hoxa5 knockout mutant. In the work reported here, functional HOXA5 protein was overexpressed in the developing nervous system in transgenic mice in order to gain insight into the mechanisms by which this gene exerts its effects during development. Evaluation of the phenotypes of F0 transgenics and transgenic animals from line Hoxa5SV2 provides strong evidence that overexpression of HOXA5 disrupts normal neural development, primarily of the dorsal horns of the spinal cord in the brachial region. Subtle effects on the peripheral nervous system have not been demonstrated here, although they are likely to occur, potentially in the forin of a secondary defect resulting from loss of interneurons with which peripheral neurons usually synapse. Although not indicative of structural vs. functional effects, evidence indicating that peripheral defects are likely to exist includes frequent skin ulceration of regions innervated from affected levels of the spinal cord, and apparent sensory defects of the forepaw. In an additional line of inquiry, line Hoxa 5SV2 was used as a tool to identify potential targets of Hoxa5 in vivo. Based on the literature and microarray analysis comparing Hoxa5SV2 embryonic mRNA expression patterns to wildtype littermates, several genes were implicated as candidates for targets of HOXA5 function, and further study was initiated on the expression of two of these candidates in Hoxa5SV2 transgenics.