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The Journal of Neuroscience, July 20, 2005, 25(29):6721-6728; doi:10.1523/JNEUROSCI.0760-05.2005

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Neurobiology of Disease
Bcl-x Is Required for Proper Development of the Mouse Substantia Nigra

Joseph M. Savitt,^1,2 Susie S. Jang,¹ Weitong Mu,⁵ Valina L. Dawson,^1,2,3,4 and Ted M. Dawson^1,2,3

¹Institute for Cell Engineering and Departments of ²Neurology, ³Neuroscience, ⁴Physiology, and ⁵Internal Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Recent findings have uncovered a role for the Bcl-x gene in the survival of dopaminergic neurons. The exact nature of this role has been difficult to examine because of the embryonic lethality of Bcl-x gene disruption in mouse models. Here we report the generation catecholaminergic cell-specific conditional Bcl-x gene knock-out mice using Cre-lox recombination technology. First we produced transgenic mice that express Cre recombinase from an exogenous rat tyrosine hydroxylase promoter (TH-Cre mice). These mice were crossed to Z/AP and Z/EG reporter mouse strains to verify catecholaminergic (TH-positive) cell-specific Cre expression. The TH-Cre mice then were mated to mice possessing the Bcl-x gene flanked by loxP sites, thereby producing offspring with Bcl-x deletion limited to catecholaminergic cells. The resulting mice are viable but have one-third fewer catecholaminergic neurons than do control animals. They demonstrate a deficiency in striatal dopamine and also tend to be smaller and have decreased brain mass when compared with controls. Surprisingly, surviving neurons were found that lacked Bcl-x immunoreactivity, thereby demonstrating that this gene is dispensable for the ongoing survival of a subpopulation of catecholaminergic cells.

Key words: Parkinson; Bcl-x; catecholamine; substantia nigra; dopamine; tyrosine hydroxylase

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Received Feb 24, 2005; revised May 31, 2005; accepted May 31, 2005.

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