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Development of Midbrain Dopamine Neurons: Role of Epigenetic Factors

Contact Person: Umberto di Porzio (diporzio@iigbna.iigb.na.cnr.it)

Discussion and Conclusion

The development of the midbrain dopaminergic system has been studied extensively. It shows how complex and varied neural functions subserved by a small group of neurons can be achieved trough the correct interplay of an intrinsic program and extrinsic environmental influences. Recent findings indicate that midbrain neural plate progenitors differentiate into DA neurons by the combined action of two extracellular inducers, Sonic hedgehog and FGF8, and that these molecules are necessary and sufficient for the early induction of DA neurons along the ventral neuraxis. We show that these events can take place also in vitro in dissociated DA neurons. Further development is achieved in vitro since Nurr 1 gene expression is modulated in mesencephalic cultures by morphogens such as retinoic acid and by depolarization. Thus Nurr 1 could be the point of convergence between retinoids and activity-dependent signaling pathways. Since depolarization mimics electrical activity in vivo, which is known to influence neuronal differentiation and stabilization of functional synaptic connections in the developing CNS, it is possible that electrical activity is involved in DA neuron circuit formation through modulation of Nurr 1 gene expression.

Several DA functions appear to be selectively modulated by specific interaction with the developing target tissue. Synthesis and accumulation of DA is achieved shortly after expression of Nurr 1 and Ptx3 , but DAT gene remains repressed until DA axons begin to reach their target. Only at this time DAT gene expression and functional uptake are detectable. Cell contacts between the presynaptic DA neurons and target striatal neurons are apparently necessary for the fine modulation of DAT expression and uptake function, at least in primary cultures. Thus, cell-cell interaction, which plays a key role in the development of the entire nervous system, has a crucial role in DA neuron maturation and maintenance in vivo, in vitro and in transplants.

Given the importance of neurotransmitter uptake for DA function, defect in such a transport might well be expected to underlay some neurological diseases involving dysfunction in DA neurotransmission. Indeed, an association between polymorphism at the DAT locus and ADHD has been shown (30).

Taken together, these results show that the maturation of DA neurotransmission follows a complex developmental pattern of activation of various genes, which can be selectively modulated by specific interaction with the developing target tissue in vivo and in vitro.

ACKNOWLEDGMENTS: This work was supported by grants from UILDM-Telethon (621/95), Associazione Italiana Ricerca sul Cancro, Regione Campania (L.R. 1994 n. 41), PF Biotecnologie CNR.

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di Porzio, U; Perrone-Capano, C; Da Pozzo, P; (1998). Development of Midbrain Dopamine Neurons: Role of Epigenetic Factors. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Invited Symposium. Available at URL http://www.mcmaster.ca/inabis98/
© 1998 Author(s) Hold Copyright