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Lack of the Central Nervous System- and Neural Crest-Expressed Forkhead Gene Foxs1 Affects Motor Function and Body Weight

Medical Genetics, Department of Medical Biochemistry, Göteborg University, Box 440, SE 405 30 Göteborg,¹ Unit of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, SE 171 77 Stockholm, Sweden²

Received 21 December 2004/ Returned for modification 9 March 2005/ Accepted 31 March 2005

To gain insight into the expression pattern and functional importance of the forkhead transcription factor Foxs1, we constructed a Foxs1-ß-galactosidase reporter gene "knock-in" (Foxs1^{ß-gal/ß-gal}) mouse, in which the wild-type (wt) Foxs1 allele has been inactivated and replaced by a ß-galactosidase reporter gene. Staining for ß-galactosidase activity reveals an expression pattern encompassing neural crest-derived cells, e.g., cranial and dorsal root ganglia as well as several other cell populations in the central nervous system (CNS), most prominently the internal granule layer of cerebellum. Other sites of expression include the lachrymal gland, outer nuclear layer of retina, enteric ganglion neurons, and a subset of thalamic and hypothalamic nuclei. In the CNS, blood vessel-associated smooth muscle cells and pericytes stain positive for Foxs1. Foxs1^{ß-gal/ß-gal} mice perform significantly better (P < 0.01) on a rotating rod than do wt littermates. We have also noted a lower body weight gain (P < 0.05) in Foxs1^{ß-gal/lß-gal} males on a high-fat diet, and we speculate that dorsomedial hypothalamic neurons, expressing Foxs1, could play a role in regulating body weight via regulation of sympathetic outflow. In support of this, we observed increased levels of uncoupling protein 1 mRNA in Foxs1^{ß-gal/ß-gal} mice. This points toward a role for Foxs1 in the integration and processing of neuronal signals of importance for energy turnover and motor function.