Identification and characterization of genes preferentially expressed in embryonic telencephalon and CNS stem cells

Faedo, Andrea (2004). Identification and characterization of genes preferentially expressed in embryonic telencephalon and CNS stem cells. PhD thesis The Open University.



One of the major goals in developmental neurobiology is to unravel the molecular programs controlling telencephalic development and neural differentiation. The complexity of brain cell types and circuits is reflected in the complexity of gene expression patterns in the brain. It is believed that perhaps a third to half of all genes are largely or exclusively dedicated to directing development, maintenance and functioning of the brain. In mammals, formation of the complex brain structure occurs over the long period of prenatal development. During this period neural progenitor cells must be instructed to undergo proper proliferation, migration, differentiation and connectivity.

The aim of my study was to identify genes, within a collection of novel genes preferentially expressed in the embryonic telencephalon, controlling such processed in the mammalian forebrain.

To this aim, as a preliminary step, an EST sequencing approach has been undertaken to catalogue and array the repertoire of genes represented in a subtractive library optimized to select rate or unique cDNAs preferentially expressed in the E14.5 mouse telencephalon (named "Telencephalic Embryonic Subtracted Sequences" (Porteus et al., 1992)). The hypothesis driving the production of such a library was that genes preferentially expressed during embryogenesis are likely to be specifically involved in the development of the telencephalon and in the biology of the neural progenitor cells. The selected transcriptome of 1026 unique cDNAs has been used to generate a unique microarray, and to perform gene expression profiling experiments on:
(i) mice mutant for transcription factors involved in forebrain development (D1x1/2, Nkx2.1, Pax6, Ngn1/2),
(ii) in vitro cultured neural stem cells, committed neural progenitor cells (transient amplifying) and terminally differentiated neural cells.

The analysis of the resulting expression profiles has allowed the identification of novel genes that are candidates for playing a major role in neurogenesis and telencephalic development.

The differential expression identified with the Tess has been validated using RNA in situ hybridization on embryonic tissue. Two novel genes (corresponding to Tess 28.8E and Tess 31.5E) have been found to be specifically down regulated in D1x1/2-/- subpallium (-46,51 fold for 28.8E; -6,44 fold for 31.5E), and up regulated in Pax6-/- (4,34 for 28.8E; 3,15 for 31.5E) and Ngn1/2-/- (9,02 for 28.8e; 5,04 for 31.5E) pallium

The microarray experiments on neural stem cells allowed the identification of a selection of genes putatively involved in the process of self-renewal, lineage commitment and differentiation. Some of these genes have been analysed by RNA in situ hybridizations and demonstrated interesting restricted expression patterns in the developing telencephalon.

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