NSCL-1 and NSCL-2 synergistically determine the fate of GnRH-1 neurons and control necdin gene expression.
To study the role of the bHLH genes NSCL-1 and NSCL-2 in the development of GnRH-1 neurons, we have generated compound mutant mice. Mutant animals die at birth and show a virtually complete absence of GnRH-1 neurons in the posterior parts of the brain at E18.5 and an aberrant morphology of the remaining GnRH-1 neurons in the anterior parts of the brain indicating that NSCL-1 and NSCL-2 might concomitantly control differentiation/migration of GnRH-1 neurons in a cell autonomous manner. To gain further insights into this process, we screened for NSCL target genes using DNA array hybridization and detected necdin, which is deleted in the human Prader-Willi syndrome phenotypically resembling the NSCL-2 mutation. Using chromatin immunoprecipitation and site-directed mutagenesis of the necdin promoter, we demonstrate that NSCLs together with additional cofactors directly control transcription of the necdin gene. NSCL-dependent control of necdin expression might be instrumental for proper neuronal cell differentiation and enable GnRH-1 neurons to migrate.
Krüger
Marcus
M
Institute of Physiological Chemistry, University of Halle-Wittenberg, Halle 06097, Germany.
Ruschke
Karen
K
Braun
Thomas
T
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation; D020868:Gene Silencing; D005865:Gestational Age; D007987:Gonadotropin-Releasing Hormone / Q000737:chemistry / Q000378:metabolism*; D007031:Hypothalamus / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011247:Pregnancy; D011401:Promoter Regions, Genetic
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D007987:Gonadotropin-Releasing Hormone; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C498272:Nhlh1 protein, mouse; C484104:Nhlh2 protein, mouse; C069766:necdin