ALTERED FOREBRAIN AND HINDBRAIN DEVELOPMENT IN MICE MUTANT FOR THE GSH-2 HOMEOBOX GENE

The patterning of the mammalian brain is orchestrated by a large batte ry of regulatory genes. Here we examine the developmental function of the Gsh-2 nonclustered homeobox gene. Whole-mount and serial section i n situ hybridizations have been used to better define Gsh-2 expression domains within the developing forebrain, midbrain, and hindbrain. Gsh -2 transcripts are shown to be particularly abundant in the hindbrain and within the developing ganglionic eminences of the forebrain. In ad dition, mice carrying a targeted mutation of Gsh-e have been generated and characterized. Homozygous mutants uniformly failed to survive mor e than 1 day following birth. At the physiologic level the mutants exp erienced apnea and reduced levels of hemoglobin oxygenation. Histologi cally, the mutant brains had striking alterations of discrete componen ts. In the forebrain the lateral ganglionic eminence was reduced in si ze. In the hindbrain, the area postrema, an important cardiorespirator y chemosensory center, was absent. The contiguous nucleus tractus soli tarius, involved in integrating sensory input to maintain homeostasis, was also severely malformed in mutants. Immunohistochemistry was used to examine the mutant brains for alterations in the distribution of m arkers specific for serotonergic and cholinergic neurons. In addition, in situ hybridizations were used to define expression patterns of the Dir 2 and Nkx 2.1 homeobox genes in Gsh-2 mutant mice. The mutant lat eral ganglionic eminences showed an abnormal absence of Dir 2 expressi on. These results better define the genetic program of development of the mammalian brain, support neuromeric models of brain development, a nd further suggest similar patterning function for homeobox genes in p hylogenetically diverse organisms. (C) 1997 Academic Press.