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Vol. 13, No. 21, pp. 2787-2800, November 1, 1999
1 International Institute of Genetics and Biophysics,
Consiglio Nationale delle Ricerche (CNR), 80125 Naples, Italy;
2 Yale University, Child Study Center, New Haven, Connecticut
06520 USA; 3 Service de Génétique Médicale,
Hôpital Sainte-Justine, Université de Montréal,
Montréal (Québec) H3T 1C5, Canada
Development of the neuroendocrine hypothalamus is characterized by a
precise series of morphogenetic milestones culminating in terminal
differentiation of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed
in neurons giving rise to the paraventricular (PVN), supraoptic (SON),
anterior periventricular (aPV), and arcuate (ARN) nuclei throughout
their development. Homozygous
Otp
/ mice die soon after birth
and display progressive impairment of crucial neuroendocrine
developmental events such as reduced cell proliferation, abnormal cell
migration, and failure in terminal differentiation of the parvocellular
and magnocellular neurons of the aPV, PVN, SON, and ARN. Moreover, our
data provide evidence that Otp and Sim1, a bHLH-PAS
transcription factor that directs terminal differentiation of the PVN,
SON, and aPV, act in parallel and are both required to maintain
Brn2 expression which, in turn, is required for neuronal cell
lineages secreting oxytocin (OT), arginine vasopressin (AVP), and
corticotropin-releasing hormone (CRH).
[Key Words: Orthopedia; cell migration; cell proliferation; neuroendocrine hypothalamus; terminal differentiation]
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