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The role of SOX9 in neural progenitor identity

Nunn, AC; (2012) The role of SOX9 in neural progenitor identity. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Recent evidence has shown that SOX9 is required for the proliferation and multipotentiality of neural progenitors in the developing CNS. Notably, these findings suggest that in contrast to previous studies, SOX9 is important for differentiation along the neuronal lineage, both in the adult and embryonic CNS. Here, a phenotypic analysis of the CNS-specific Sox9-null forebrain, including detailed analysis of cortical lamination, shows that neurons of the appropriate layer-identity are born and migrate to their destined layers. All other parameters in this analysis were normal, with the exception of the formation of glia from the ventral and dorsal telencephalons, and midline glial structures, which were absent in the mutant. Since Sox9 is expressed long before the onset of gliogenesis in these brain regions, the possibility that Sox9 may ‘prime’ the progenitors of the ventricular zone to respond to a gliogenic signal arose. To investigate this, populations of Sox9-deficient and wild-type dorsal telencephalon cells were enriched for progenitors and subjected to transcriptional profiling. Bioinformatic analysis revealed that ‘vascular endothelial growth factor’ receptors, which are important for gliogenesis, were down-regulated, in addition to two transcription factors. Previously, Sox9-deficient neural progenitors have been shown to generate neurospheres poorly, and so the dataset of potential targets was used to identify candidates that might mediate this reduced neurosphere-forming ability. Thirteen down-regulated targets were confirmed by qPCR, six of which were expressed in the same distribution as Sox9 in the embryonic telencephalon; three were also expressed in neurosphere cultures. Of these, one encoded a K+ channel (Kir4.1), and the other a modulator of the GABAA channel (DBI). In order to show that reduced expression of one of these might contribute to the Sox9-deficient neurosphere phenotype, pharmacological modulators were used and showed that blockade of Kir4.1 or enhancement of GABAA channels mimicked the effect of Sox9 loss, leaving open the possibility that Kir4.1 or DBI expression might mediate this effect.

Type: Thesis (Doctoral)
Title: The role of SOX9 in neural progenitor identity
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright restricted material has been removed from the e-thesis.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
URI: http://discovery.ucl.ac.uk/id/eprint/1372652
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