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Vol. 12, No. 20, pp. 3264-3275, October 15, 1998
1 Department of Embryology, Carnegie Institution of
Washington, Baltimore, Maryland 21210 USA;
2 Department of
Pharmacological Sciences, State University of New York at Stony Brook,
Stony Brook, New York 11794-8651 USA
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.
[Key Words: SIM; hypothalamus; paraventricular nucleus; supraoptic nucleus; hormones]
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