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

Abstract

To gain insight into the expression pattern and functional importance of the forkhead transcription factor Foxs1, we constructed a Foxs1-β-galactosidase reporter gene “knock-in” (Foxs1^{β-gal/β-gal}) mouse, in which the wild-type (wt) Foxs1 allele has been inactivated and replaced by a β-galactosidase reporter gene. Staining for β-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^{β-gal/β-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^{β-gal/lβ-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^{β-gal/β-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.

ACKNOWLEDGMENTS

pCH110-nls plasmid was a kind gift from Jean-Jacques Panthier. ES cell culture work and blastocyst injections were performed by the Transgenic Core Facility at Göteborg University.

This work was supported by the Swedish Research Council (grants K2002-04X-03522-31D and K2002-31X-12186-06A to S.E. and K2004-32X-11283-10A to P.E.), EU grants (QLK3-CT-2002-02149 and LSHM-CT-2003-503041 to S.E.), The Arne and IngaBritt Foundation and The Söderberg Foundation (to S.E.), and Petrus and Augusta Hedlunds Foundation (to P.E.).