Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1.
The bHLH-PAS transcription factor SIM1 is expressed during the development of the hypothalamic-pituitary axis in three hypothalamic nuclei: the paraventricular nucleus (PVN), the anterior periventricular nucleus (aPV), and the supraoptic nucleus (SON). To investigate Sim1 function in the hypothalamus, we produced mice carrying a null allele of Sim1 by gene targeting. Homozygous mutant mice die shortly after birth. Histological analysis shows that the PVN and the SON of these mice are hypocellular. At least five distinct types of secretory neurons, identified by the expression of oxytocin, vasopressin, thyrotropin-releasing hormone, corticotropin-releasing hormone, and somatostatin, are absent in the mutant PVN, aPV, and SON. Moreover, we show that SIM1 controls the development of these secretory neurons at the final stages of their differentiation. A subset of these neuronal lineages in the PVN/SON are also missing in mice bearing a mutation in the POU transcription factor BRN2. We provide evidence that, during development of the Sim1 mutant hypothalamus, the prospective PVN/SON region fails to express Brn2. Our results strongly indicate that SIM1 functions upstream to maintain Brn2 expression, which in turn directs the terminal differentiation of specific neuroendocrine lineages within the PVN/SON.
Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland 21210 USA.
J L
JL
Michaud
T
T
Rosenquist
N R
NR
May
C M
CM
Fan
D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins; D007031:Hypothalamus / Q000254:growth & development / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009474:Neurons / Q000473:pathology; D009490:Neurosecretory Systems / Q000196:embryology / Q000254:growth & development* / Q000473:pathology; D050809:POU Domain Factors; D010286:Paraventricular Hypothalamic Nucleus / Q000254:growth & development / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D013495:Supraoptic Nucleus / Q000254:growth & development / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D050809:POU Domain Factors; D012097:Repressor Proteins; D014157:Transcription Factors; C101750:Sim1 protein, mouse; C085076:transcription factor Brn-2