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The Journal of Neuroscience, September 1, 2000, 20(17):6501-6516

Defects of Tyrosine Hydroxylase-Immunoreactive Neurons in the Brains of Mice Lacking the Transcription Factor Pax6

Tania Vitalis¹, Olivier Cases^{1, 2}, Dieter Engelkamp³, Catherine Verney², and David J. Price¹

¹ Department of Biomedical Sciences, Medical School, Edinburgh EH8 9AG, Scotland, ² Institut National de la Santé et de la Recherche Médicale U106, Hôpital de la Salpêtrière, 75651 Paris Cedex 13, France, and ³ Medical Research Council Human Genetics Unit, Western General Hospital, Edinburgh, EH4 2XU, Scotland

In the CNS, the lack of the transcription factor Pax6 has been associated with early defects in cell proliferation, cell specification, and axonal pathfinding of discrete neuronal populations. In this study, we show that Pax6 is expressed in discrete catecholaminergic neuronal populations of the developing ventral thalamus, hypothalamus, and telencephalon. In mice lacking Pax6, these catecholaminergic populations develop abnormally: those in the telencephalon are reduced in cell number or absent, whereas those in the ventral thalamus and hypothalamus are greatly displaced and densely packed. Catecholaminergic neurons of the substantia nigra (SN) and the ventral tegmental area (VTA) do not express Pax6 protein. Nevertheless, mice lacking Pax6 display an altered pathfinding of SN-VTA projections: instead of following the route of the medial forebrain bundle ventrally, most of the SN-VTA projections are deflected dorsorostrally at the pretectal-dorsal thalamic transition zone and in the dorsal thalamic alar plate. Moreover, some catecholaminergic neurons are displaced dorsally to an ectopic location at the pretectal-dorsal thalamic transition zone. Interestingly, from the pretectal-dorsal thalamic to the dorsal thalamic-ventral thalamic transition zones, mice lacking Pax6 display an ectopic ventral to dorsal expansion of the chemorepellant/chemoattractive molecule, Netrin-1. This may be responsible for both the altered pathway of catecholaminergic fibers and the ectopic location of catecholaminergic neurons in this region.

Key words: catecholaminergic neuron; Pax6; netrin; proliferation; adhesion; axonal pathfinding

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Copyright © 2000 Society for Neuroscience  0270-6474/00/20176501-16$05.00/0

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