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Type: Thesis
Title: Sox3 dosage regulation is important for roof plate specification during central nervous system development.
Author: Lee, Kristie Pan Yu
Issue Date: 2011
School/Discipline: School of Molecular and Biomedical Science
Abstract: The central nervous system (CNS) is one of the most complicated organs in the body. Its development requires spatially and temporally dynamic but yet coordinated proliferation and differentiation of neural progenitors in order to allow the formation of the neural tube (NT) from a sheet-like neural plate, as well as the specification of different CNS domains from a homogeneous group of neural precursors. A number of genes have been identified to be important for the robust genetic and molecular regulation of the CNS development. One of these genes is SOX3, which encodes a SOX family transcription factor within a single exon. In humans, SOX3 duplications and mutations have been implicated in X-linked hypopituitarism (XH) with variable mental retardation, suggesting that CNS development is sensitive to SOX3 dosage. To recapitulate the condition in XH patients with SOX3 duplications, a transgenic Sox3 over-expression mouse model was generated in the Thomas laboratory. Two Sox3 transgenic lines were established. Intriguingly, they presented not with XH associated phenotypes, but with hallmarks of hydrocephalus. This thesis focuses on the characterisation of the hydrocephalus phenotype and the elucidation of the molecular pathogenesis that underlines the defect. Comprehensive morphological and expression analyses of single hemizygous and double hemizygous (mice with two transgene alleles, one from each Sox3 transgenic line) Sox3 transgenic mice demonstrated that the hydrocephalus has a congenital origin (congenital hydrocephalus, CH) and is associated with defective development of the subcommissural organ (SCO), a diencephalic roof plate (RP) derivative that has previously been implicated in CH. Moreover, both the CH and the SCO dysmorphology of Sox3 transgenic mice are dependent on Sox3 dosage. In addition to the SCO, defective development was also identified in other diencephalic RP derivatives in Sox3 double hemizygous embryos. In fact, SCO maldevelopment appears to be the consequence of a general RP defect, in which the identity of the RP cells (or SCO precursors) is lost and is coupled with an elevation of cellular proliferation. Further molecular analysis of the SCO development supported that Sox3 overexpression leads to the loss of RP cellular identity as the expression of genes implicated in both Bmp and Wnt signalling pathways, which are important for normal RP development, were significantly downregulated in Sox3 transgenic embryos. In addition to its role as the precursor of RP derivatives, the RP is also essential to maintain dorsal identity for proper DV patterning within the NT. Moreover, dorsal NT patterning was disrupted within the developing Sox3 transgenic embryos. Together these suggest that the Sox3 overdosage leads to the loss of RP identity and the failure of RP dependent processes. In summary, this thesis indicates that, at least in the mouse, Sox3 dosage regulation is important for proper RP development. In fact, a low level of Sox3 is permissive for RP specification. It is not known what cellular identity is taken up by the RP cells in the Sox3 double hemizygous embryos. However, given endogenous Sox3 is highly expressed in the lateral tissue that flanks the RP, it is logical to propose that the RP cells of Sox3 double hemizygous embryos may take on a cellular identity similar to their laterally neighbouring tissue. Interestingly, a CNS defect that may be due to RP dysfunction has been identified in some XH patients with SOX3 duplications, suggesting that SOX3 may have similar role in humans. CH is a heterogeneous disorder in which identification of its genetic basis in humans is difficult. This thesis proposes SOX3 as a candidate gene for CH and other RP associated defects in humans, which may assist the development of relevant prognostic techniques for clinical application.
Advisor: Thomas, Paul Quinton
Jensen, Kirk Blomquist
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2011
Keywords: Sox3; roof plate; central nervous system development; brain development; hydrocephalus
Provenance: Copyright material removed from digital thesis. See print copy in University of Adelaide Library for full text.
Appears in Collections:Research Theses

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