Progressive impairment of developing neuroendocrine cell lineages in the hypothalamus of mice lacking the Orthopedia gene

Development of the neuroendocrine hypothalamus is characterized by a precis e series of morphogenetic milestones culminating in terminal differentiatio n of neurosecretory cell lineages. The homeobox-containing gene Orthopedia (Otp) is expressed in neurons giving rise to the paraventricular (PVN), sup raoptic (SON), anterior periventricular (aPV), and arcuate (ARN) nuclei thr oughout their development. Homozygous Otp(-/-) mice die soon after birth an d display progressive impairment of crucial neuroendocrine developmental ev ents such as reduced cell proliferation, abnormal cell migration, and failu re in terminal differentiation of the parvocellular and magnocellular neuro ns of the aPV, PVN, SON, and ARN. Moreover, our data provide evidence that Otp and Sim1, a bHLH-PAS transcription factor that directs terminal differe ntiation 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 lin eages secreting oxytocin (OT), arginine vasopressin (AVP), and corticotropi n-releasing hormone (CRH).