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Function and regulation of Platelet-Derived Growth Factor Receptor Alpha during development

Sun, Tao; (1999) Function and regulation of Platelet-Derived Growth Factor Receptor Alpha during development. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Platelet-Derived Growth Factor Receptor Alpha (PDGFR[alpha]) plays a vital role in the development of vertebrate embryos, since mice lacking this protein die at mid-gestation. The PDGFR[alpha] gene displays a complex time-and tissue-specific expression pattern during development, and participates in the development of many diverse tissues and organs. Among its many functions, PDGFR[alpha] is essential for the development of oligodendrocyte progenitors (OLPs), which originate from the ventral spinal cord in the central nervous system (CNS). To gain more insight into the transcriptional regulation of the PDGFR[alpha] gene, I analyzed the relative promoter activities of a 6 kb upstream fragment of the murine PDGFR[alpha] promoter and a 2.2 kb human PDGFR[alpha] promoter by transient transfection assay in CG4 cells, an OLP cell line. I also mapped the transcription start site of PDGFR[alpha] in OLPs by primer extension and nuclease-S1 protection assay. These results suggest that distant cis-acting regulatory elements are required for PDGFR[alpha] expression in OLPs. To study PDGFR[alpha] regulation, particularly in OLPs, I generated a transgenic mouse model by pronuclear injection of a 380 kb yeast artificial chromosome (YAC) containing the entire human PDGFR[alpha] gene and flanking sequences. The human PDGFR[alpha] transgene was faithfully expressed in OLPs in the spinal cord, which is not observed with conventional transgenes containing up to 6 kb of 5 flanking sequence, and also in many tissues outside of the CNS. There was also ectopic expression at sites that normally express c-kit and flk-1, which map close downstream of PDGFR[alpha]. Despite this, the YAC transgene rescued the profound craniofacial abnormalities and spina bifida in the PDGFR[alpha] null mutant mouse and prolonged survival until birth. In addition, PDGFR[alpha] null mice rescued with the YAC transgene died after birth from respiratory failure. Furthermore, I also investigated the role of transcription factor Pax6 in specification of OLPs and motor neurons (MNs) in the ventral spinal cord. I found that OLPs originated in the ventral-most part of the Pax6-positive ventricular zone, which at earlier times generated somatic (Isl2/Lim3-positive) MNs. In Pax6 mutant mice, the site of origin of OLPs was shifted dorsally and production of both OLPs and MNs was delayed by about a day. I suggest that OLPs and somatic MNs are derived from the same pool of precursors whose positional specification depends on Pax6. Neuron-glia fate switching might be a preprogrammed property of these precursors or a response to feedback from newly generated neurons. Oligodendrocytes developed normally in explants of Isll(-/-) spinal cords, which lack MNs, arguing against feedback control. I suggest that the neuron-glia switch is an intrinsic developmental program in a specific subset of neural precursors.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Function and regulation of Platelet-Derived Growth Factor Receptor Alpha during development
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
URI: https://discovery.ucl.ac.uk/id/eprint/10101288
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