| Dissertation |
Thesis (Ph.D.) --NUI, 2004 at Department of Anatomy, UCC. |
| Summary |
Growth differentiation factor-5 (GDF-5) is a member of the transforming growth factor-β superfamily, a family of proteins that play diverse roles in many aspects of cell growth, proliferation and differentiation. GDF-5 has also been shown to be a trophic factor for embryonic midbrain dopaminergic neurons in vitro (Krieglstein et al. 1995) and after transplantation to adult rats in vivo (Sullivan et al. 1998). GDF-5 has also been shown to have neuroprotective and neurorestorative effects on adult dopaminergic neurons in the substantia nigra in animal models of Parkinson's disease (Sullivan et al. 1997, 1999; Hurley et al. 2004). This experimental evidence has lead to GDF-5 being proposed as a neurotrophic factor with potential for use in the treatment of Parkinson's disease. However, it is not known if GDF-5 is expressed in the brain and whether it plays a role in dopaminergic neuron development. The experiments presented here aim to address these questions. To that end this thesis is divided into five separate studies each addressing a particular question associated with GDF-5 and its expression patterns and roles during the development of the rat midbrain. Expression of the GDF-5 in the developing rat ventral mesencephalon (VM) was found to begin at E12 and peak on E14, the day that dopaminergic neurons undergo terminal differentiation. In the adult rat, GDF-5 was found to be restricted to heart and brain, being expressed in many areas of the brain, including striatum and midbrain. This indicated a role for GDF-5 in the development and maintenance of dopaminergic neurons. The appropriate receptors for GDF-5 (BMPR-II and BMPR-Ib) were found to be expressed at high levels in the rat VM at E14 and BMPR-II expression was demonstrated on dopaminergic neurons in the E13 mouse VM. GDF-5 resulted in a three-fold increase in the numbers of dopaminergic neurons in cultures of E14 rat VM, without affecting the numbers of neurones or total cells. GDF-5 was found to increase the proportion of neurons that were dopaminergic. The numbers of Nurrl-possitive cells were not affected by GDF-5 treatment, but GDF-5 did increase the numbers of Nurrl-positive cells that expressed tyrosine hydroxylase (TH). Taken together these data indicated that GDF-5 increases the conversion of Nurrl positive, TH negative cells to Nurrl positive, TH-positive cells. In GDF-5 treated cultures, total neurite length, neurite arborisation and somal area of dopaminergic neurons were all significantly increased compared to control cultures. Thus this study showed that GDF-5 increases the numbers and morphological differentiation of VM dopaminergic neurons in vitro. |
| Add Form |
Also available online via CORA |
| Subject |
Nervous system -- Degeneration.
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Nervous system -- Regeneration.
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| Collection |
Theses Ph.D.
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Theses Anatomy Department
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CORA
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| Description |
200 p. : ill., ; 30 cm. |
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