Defective development of secretory neurones in the hypothalamus of Arnt2-knockout mice

Background: Within the basic region-helix-loop-helix (bHLH)-PAS family of t ranscription factors, Arnt and Arnt2 play unique roles; these two factors n ot only heterodimerize with themselves, but also with other members of this family and they act as transcription regulators which bind to specific DNA elements. Whereas Arnt is broadly expressed in various tissues, the expres sion of Arnt2 is known to be limited to the neural tissues. Results: To elucidate the function of Arnt2 in detail, we cloned the mouse Arnt2 gene and its gene structure was determined. We subsequently generated germ line Arnt2 mutant mice by gene targeting technology. Heterozygous Arn t2 mice were viable, but homozygous Arnt2 gene knockout mice died shortly a fter birth. Histological and immunological analyses revealed that the supra optic nuclei (SON) and the paraventricular nuclei (PVN) are hypocellular. M oreover, secretory neurones identified by the expression of neurosecretory hormone such as arginine vasopressin, oxytocin, corticotrophin-releasing ho rmone and somatostatin are completely absent in SON and PVN in the mutant A rnt2 mice. Consistent with these observations, prospective SON and PVN neur ones which express Brn2 appeared around E13.5 in the mantle zone, but no ne urones which expressed the neurosecretory hormones were found in the SON an d PVN regions. Conclusions: These data show that the transcription factor Arnt2 controls t he development of the secretory neurones at the later or final stages of di fferentiation rather than at the beginning stage. Strikingly similar observ ations have been reported with the Sim1 deficient mice. Taken together, our results demonstrate that Arnt2 is an indispensable transcription factor fo r the development of the hypothalamus, and suggest that Arnt2 is an obligat ory partner molecule of Sim1 in the developmental process of the neuroendoc rinological cell lineages.