Abstract
The molecular mechanisms regulating neurogenesis involve the control of gene expression by transcription factors. Gbx1 and Gbx2, two members of the Gbx family of homeodomain-containing transcription factors, are known for their essential roles in central nervous system development. The expression domains of mouse Gbx1 and Gbx2 include regions of the forebrain, anterior hindbrain, and spinal cord. In the spinal cord, Gbx1 and Gbx2 are expressed in PAX2+ interneurons of the dorsal horn and ventral motor neuron progenitors. Based on their shared domains of expression and instances of overlap, we investigated the functional relationship between Gbx family members in the developing spinal cord using Gbx1−/−, Gbx2−/−, and Gbx1−/−/Gbx2−/− embryos. In situ hybridization analyses of embryonic spinal cords show upregulation of Gbx2 expression in Gbx1−/− embryos and upregulation of Gbx1 expression in Gbx2−/− embryos. Additionally, our data demonstrate that Gbx genes regulate development of a subset of PAX2+ dorsal inhibitory interneurons. While we observe no difference in overall proliferative status of the developing ependymal layer, expansion of proliferative cells into the anatomically defined mantle zone occurs in Gbx mutants. Lastly, our data shows a marked increase in apoptotic cell death in the ventral spinal cord of Gbx mutants during mid-embryonic stages. While our studies reveal that both members of the Gbx gene family are involved in development of subsets of PAX2+ dorsal interneurons and survival of ventral motor neurons, Gbx1 and Gbx2 are not sufficient to genetically compensate for the loss of one another. Thus, our studies provide novel insight to the relationship harbored between Gbx1 and Gbx2 in spinal cord development.
Highlights
The dorsal and ventral regions of the spinal cord are functionally and anatomically distinct, interacting through complex neuronal circuits
A significant role for gastrulation brain homeobox (Gbx) transcription factors in neural development has been established. While their mRNA expression in the spinal cord overlap spatially and temporally, they are not biochemically identical. Whereas both Gbx1 and Gbx2 are heavily expressed in the dorsal mantle zone at E12.5, Gbx2 expression diminishes after E13.5 [30] (Figure 1), while Gbx1 expression persists through postnatal stages
Key in understanding phenotypic differences and similarities in Gbx homozygous null mutants and relative functions of Gbx1 and Gbx2 in spinal cord development [19,20,25,35,36], is whether the observed loss-of-function phenotypes are determined by differences in spatial and temporal expression or biochemical differences between the proteins
Summary
The dorsal and ventral regions of the spinal cord are functionally and anatomically distinct, interacting through complex neuronal circuits. Of neuronal circuits in the spinal cord depends on specification and patterning of distinct neurons in the dorsal and ventral horns [1,2]. It has become clear that many essential aspects of the developmental programing are directed by restricted expression profiles of transcription factors in a cell type specific manner [3,4,5,6].
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