Differential requirements for neurogenin 3 in the development of POMC and NPY neurons in the hypothalamus.

The neuroendocrine hypothalamus regulates a spectrum of essential biological processes and underlies a range of diseases from growth failure to obesity. While the exploration of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, very little is known about the processes underlying the genesis and specification of the neurons in the arcuate and ventromedial nuclei. Recent studies demonstrate that the proneural basic helix-loop-helix transcription factor Mash1 is required for neurogenesis and neuronal subtype specification in the ventral hypothalamus. We demonstrate here that Ngn3, another basic helix-loop-helix transcription factor, is expressed in mitotic progenitors in the arcuate and ventromedial hypothalamic regions of mouse embryos from embryonic days 9.5-17.5. Genetic fate mapping and loss of function studies in mice demonstrate that Ngn3+ progenitors contribute to subsets of POMC, NPY, TH and SF1 neurons and is required for the specification of these neuronal subtypes in the ventral hypothalamus. Interestingly, while Ngn3 promotes the development of arcuate POMC and ventromedial SF1 neurons, it inhibits the development of NPY and TH neurons in the arcuate nuclei. Given the opposing roles of POMC and NPY neurons in regulating food intake, these results indicate that Ngn3 plays a central role in the generation of neuronal populations controlling energy homeostasis in mice.

Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells.

The neuroendocrine hypothalamus regulates a number of critical biological processes and underlies a range of diseases from growth failure to obesity. Although the elucidation of hypothalamic function has progressed well, knowledge of hypothalamic development is poor. In particular, little is known about the processes underlying the neurogenesis and specification of neurons of the ventral nuclei, the arcuate and ventromedial nuclei. The proneural gene Mash1 is expressed throughout the basal retrochiasmatic neuroepithelium and loss of Mash1 results in hypoplasia of both the arcuate and ventromedial nuclei. These defects are due to a failure of neurogenesis and apoptosis, a defect that can be rescued by ectopic Ngn2 under the control of the Mash1 promoter. In addition to its role in neurogenesis, analysis of Mash1(-/-), Mash1(+/-), Mash1(KINgn2/KINgn2), and Mash1(KINgn2/+) mice demonstrates that Mash1 is specifically required for Gsh1 expression and subsequent GHRH expression, positively regulates SF1 expression, and suppresses both tyrosine hydroxylase (TH) and neuropeptide Y (NPY) expression. Although Mash1 is not required for propiomelanocortin (POMC) expression, it is required for normal development of POMC(+) neurons. These data demonstrate that Mash1 is both required for the generation of ventral neuroendocrine neurons as well as playing a central role in subtype specification of these neurons.

Conditional deletion of neurogenin-3 using Nkx2.1iCre results in a mouse model for the central control of feeding, activity and obesity.

The ventral hypothalamus acts to integrate visceral and systemic information to control energy balance. The basic helix-loop-helix transcription factor neurogenin-3 (Ngn3) is required for pancreatic ß-cell development and has been implicated in neuronal development in the hypothalamus. Here, we demonstrate that early embryonic hypothalamic inactivation of Ngn3 (also known as Neurog3) in mice results in rapid post-weaning obesity that is associated with hyperphagia and reduced energy expenditure. This obesity is caused by loss of expression of Pomc in Pomc- and Cart-expressing (Pomc/Cart) neurons in the arcuate nucleus, indicating an incomplete specification of anorexigenic first order neurons. Furthermore, following the onset of obesity, both the arcuate and ventromedial hypothalamic nuclei become insensitive to peripheral leptin treatment. This conditional mouse mutant therefore represents a novel model system for obesity that is associated with hyperphagia and underactivity, and sheds new light upon the roles of Ngn3 in the specification of hypothalamic neurons controlling energy balance.