Developmental Transcription Factors in Dopamine Ne.. (Dopamine Neuron Code)
Developmental Transcription Factors in Dopamine Neuron Maintenance
(Dopamine Neuron Code)
Date du début: 1 juil. 2010,
Date de fin: 31 déc. 2012
Understanding mechanisms underlying the generation of diverse neuronal subtypes is one of the major challenges in current neuroscience research. Our interest is focused on midbrain dopamine (mdDA) neurons. These cells are essential for the control of multiple brain functions, including movement, emotion and reward, and dysfunction is involved in the pathogenesis of several mental and neurological disorders including Parkinson’s disease (PD). Extensive studies have identified critical regulatory pathways in cell fate specification and differentiation of mdDA neurons. Several transcription factors with well-established roles in such early events continue to be expressed in neurons at late maturation and in the adult. However, virtually no information on how they function at these late stages is available for any neuron type, including mdDA neurons. Since mutations have been identified in some of these factors in cases of PD it can be speculated that they contribute to a transcription factor network that is essential for maintaining the integrity of adult mdDA neurons. The aim of this project is to characterize the function of transcription factors expressed in late maturation and adult mdDA neurons. The following main approaches will be taken: i) comprehensive expression analyses in the mouse of mdDA neuron developmental transcription factors at late maturation and adult stages; ii) analysis of gene expression and promoter occupancy in postmitotic mdDA neurons derived from mouse embryonic stem cells after genetic manipulation by lentiviral vectors; iii) usage of conditional gene targeting in mouse for late ablation of transcription factor genes followed by comprehensive phenotypic analyses. Taken together we envision that these studies will begin to elucidate a transcription factor network that contributes to the maintenance and plasticity of neurons, and will be relevant for understanding neurodegenerative diseases and for advancing methods in regenerative medicine.
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