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The Journal of Neuroscience, August 19, 2009, 29(33):10449-10459; doi:10.1523/JNEUROSCI.3048-09.2009

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 Previous Article

Development/Plasticity/Repair
Subtype Specification of GABAergic Amacrine Cells by the Orphan Nuclear Receptor Nr4a2/Nurr1

Haisong Jiang1,2,3 and Mengqing Xiang1,2,3

1Center for Advanced Biotechnology and Medicine, 2Department of Pediatrics, and 3Graduate Program in Molecular Genetics and Microbiology, University of Medicine and Dentistry of New Jersey–Robert Wood Johnson Medical School, Piscataway, New Jersey 08854

Correspondence should be addressed to Dr. Mengqing Xiang, Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ 08854. Email: xiang{at}cabm.rutgers.edu

In the mammalian retina, amacrine cells (ACs) contain numerous subtypes with extremely diverse morphologies and physiological functions. To date, how these subtypes arise during retinogenesis remains largely unknown at the molecular level. The orphan nuclear receptor Nr4a2 plays an essential role in specifying ventral midbrain dopaminergic neurons, and its mutations are associated with familial Parkinson's disease. Here we show that Nr4a2 is also critically involved in the specification of AC subtype identity. During mouse retinogenesis, Nr4a2 is expressed in a subset of postmitotic GABAergic ACs and their precursors. Its targeted inactivation results in the loss of a subpopulation of GABAergic ACs that include all dopaminergic and p57Kip2+ neurons as well as a simultaneous increase of calbindin+ ACs. Misexpressed Nr4a2 can promote GABAergic AC differentiation and repress calbindin+ ACs, whereas its dominant-negative form has the ability to suppress the GABAergic AC fate. Moreover, the expression of Nr4a2 is positively regulated by Foxn4 and negatively controlled by Brn3b, two retinogenic factors previously shown to promote and suppress GABAergic ACs, respectively. These data suggest that Nr4a2 is both necessary and sufficient to confer AC precursors with the identity of a GABAergic AC phenotype, and that it may network with multiple other retinogenic factors to ensure proper specification and differentiation of AC neurotransmitter subtypes.

Received June 26, 2009; accepted July 21, 2009.

Correspondence should be addressed to Dr. Mengqing Xiang, Center for Advanced Biotechnology and Medicine, 679 Hoes Lane, Piscataway, NJ 08854. Email: xiang{at}cabm.rutgers.edu






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