The murine Otp homeobox gene plays an essential role in the specification of neuronal cell lineages in the developing hypothalamus

Hypothalamic nuclei, including the anterior periventricular (aPV), paravent ricular (PVN), and supraoptic (SON) nuclei strongly express the homeobox ge ne Orthopedia (Otp) during embryogenesis. Targeted inactivation of Otp in t he mouse results in the loss of these nuclei in the homozygous null neonate s. The Otp null hypothalamus fails to secrete neuropeptides somatostatin, a rginine vasopressin, oxytocin, corticotropin-releasing hormone, and thyrotr opin-releasing hormone in an appropriate spatial and temporal fashion, and leads to the death of Otp null pups shortly after birth. Failure to produce these neuropeptide hormones is evident prior to E15.5, indicating a failur e in terminal differentiation of the aPV/PVN/SON neurons. Absence of elevat ed apoptotic activity, but reduced cell proliferation together with the ect opic activation of Six3 expression in the presumptive PVN, indicates a crit ical role for Otp in terminal differentiation and maturation of these neuro endocrine cell lineages. Otp employs distinct regulatory mechanisms to modu late the expression of specific molecular markers in the developing hypotha lamus. At early embryonic stages, expression of Sim2 is immediately downreg ulated as a result of the absence of Otp, indicating a potential role for O tp as an upstream regulator of Sim2 In contrast, the regulation of Brn4 whi ch is also expressed in the SON and PVN is independent of Otp function. Hen ce no strong evidence links Otp and Brn4 in the same regulatory pathway. Th e involvement of Otp and Sim1 in specifying specific hypothalamic neurosecr etory cell lineages is shown to operate via distinct signaling pathways tha t partially overlap with Brn2. (C) 2000 Academic Press.