Stevens, Georgina Erica May; (1994) POU-domain transcription factors in the developing rat nervous system. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mature nervous system is comprised of an enormous diversity of neurons and glial cells that arise from the apparently homogeneous population of pluripotent precursor cells of the embryonic neural tube. The mechanism by which these neuroepithelial precursor cells choose their differentiated fates is not understood. We have approached this problem by studying the development of one particular glial cell lineage, the oligodendrocyte lineage. Oligodendrocytes, the myelinating cells of the central nervous system, develop from glial progenitor cells known as 0-2A progenitor cells. 0-2A progenitor cells proliferate during embryonic development and first start to give rise to post-mitotic oligodendrocytes around the day of birth in the rat. 0-2A progenitor cells express receptors for platelet derived growth factor (PDGF), and divide in response to PDGF. When an 0-2A progenitor cell takes the decision to differentiate in vivo or in vitro it still expresses functional PDGF receptors but loses the ability to divide in response to PDGF. If we could understand the nature of the molecular switch involved in the loss of PDGF-responsiveness, we might begin to understand how the timing of oligodendrocyte differentiation is controlled during development. Transcription factors must have some role in differentiation since genes are expressed in differentiated cells that are not expressed in their undifferentiated precursor cells, and vice versa. For example, oligodendrocytes express genes encoding structural myelin proteins that are not expressed in 0-2A progenitor cells. Part of this Thesis involves experiments in which I investigate the involvment of transcription factors in oligodendrocyte development. I chose to concentrate on POU-domain transcription factors because their prototypic members appear to be lineage- specific, and have been shown to have a role in regulating the expression of differentiation specific genes. Using a strategy based on the polymerase chain reaction I identified several members of this family that are expressed in 0-2A progenitor cells, and investigated how they are regulated at the RNA level when 0-2A progenitors differentiate into oligodendrocytes in vitro. These experiments suggest that a subset of POU-transcription factors may be closely coupled to the transition from proliferation to differentiation in the oligodendrocyte lineage. During these experiments I also isolated cDNAs encoding the DNA binding region of two novel members of the POU-domain family that are closely related to the unc-86 gene of the nematode worm, Caenorhabditis elegans, and to a mammalian POU-factor gene known as brn-3. Together these define a brn-3 subfamily of POU-factors whose vertebrate members we refer to as brn-3a, brn-3b and brn-3c. I have investigated the patterns of expression of this subfamily in embryonic rat by in situ hybridisation. All members are expressed exclusively in the nervous system, notably by sensory neurons in the dorsal root ganglia (DRG), and by some deep dorsal horn neurons of the spinal cord. brn-3c is expressed in tiny subpopulations of neurons in the DRG and spinal cord suggesting that brn-3 family members may be involved in specifying particular subclasses of neurons that have a sensory phenotype. Unc-86 is involved in determining the differentiated fate of cells in many neuroblast lineages and also has a function in mature neurons. Brn-3a and Brn-3c the mammalian members of the same subfamily may have similar functions since they are expressed initially in dividing neurons in the DRG and then later in post-mitotic neurons in the DRG and spinal cord. These mammalian POU-factors may therefore be involved in the regulation of development or function of subpopulations of neurons.

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