Abstract
The forkhead family is a quickly expanding family of transcription factors that are important for embryonic development. They control fundamental developmental processes by mediating the transcriptional activation of downstream effector genes. Although their importance for embryonic development is well documented, still relatively little is known about ´forkheads´ in development of
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the central nervous system. In addition to its physiological and clinical importance, the developmental pathways of the midbrain dopamine system have been studied extensively, and this system therefore provides a good model to study forkhead functions in the brain. The research described in this thesis was aimed at identifying forkhead transcription factors expressed in the midbrain dopamine system and other neural systems, and to functionally characterize selected forkhead factors in relation to brain development and related developmental processes.
We identified multiple family members in specific neural systems, including two previously unidentified forkhead factors, often displaying a remarkable preference for complex cortical structures. We have identified a novel forkhead transcription factor called Foxk2 in midbrain dopamine neurons, and found that this factor is important for cellular survival and for embryonic development. Foxk2 is expressed in various tissues, including kidney, intestines and olfactory system, often at sites of continued proliferation. In addition, Foxk2 and its human and rat orthologues are expressed in all cell lines that we examined, and have been found in multiple cases of neoplasia in mouse and human. It is constitutively expressed in proliferating and arrested cells, and is invariantly localized to the nucleus. Foxk2 deficiency leads to increased apoptosis in proliferating cells, whereas Foxk2 overexpression prevents cells from programmed cell death. Developing Xenopus embryos are severely affected and suffer from growth retardation in the absence of FoxK2. We propose a role for Foxk2 in regulation of cell survival of proliferating cells and embryonic development.
We also found that the forkhead transcription factor Foxd2 is specifically expressed in immature dopamine neurons that are migrating to their final destination, upon which Foxd2 is switched off. Detailed analysis has exposed a novel developmental origin for dopamine neurons of the substantia nigra, and these transverse and longitudinal differences in developmental origin between the substantia nigra and the ventral tegmental area may confer differential competence to respond to developmental signals. This could provide a possible cause for putative variance in cellular properties, which underlie the selective degeneration of substantia nigra neurons in Parkinson's disease.
Altogether, the research described in this thesis has demonstrated that forkhead transcription factors are differentially expressed in the developing and adult brain. Certain forkheads may be implicated in processes such as cell division and cell death, and could therefore be important for brain-related disorders.
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