Major ß cell-specific functions of NKX2.2 are mediated via the NK2-specific domain.

The consolidation of unambiguous cell fate commitment relies on the ability of transcription factors (TFs) to exert tissue-specific regulation of complex genetic networks. However, the mechanisms by which TFs establish such precise control over gene expression have remained elusive-especially in instances in which a single TF operates in two or more discrete cellular systems. In this study, we demonstrate that ß cell-specific functions of NKX2.2 are driven by the highly conserved NK2-specific domain (SD). Mutation of the endogenous NKX2.2 SD prevents the developmental progression of ß cell precursors into mature, insulin-expressing ß cells, resulting in overt neonatal diabetes. Within the adult ß cell, the SD stimulates ß cell performance through the activation and repression of a subset of NKX2.2-regulated transcripts critical for ß cell function. These irregularities in ß cell gene expression may be mediated via SD-contingent interactions with components of chromatin remodelers and the nuclear pore complex. However, in stark contrast to these pancreatic phenotypes, the SD is entirely dispensable for the development of NKX2.2-dependent cell types within the CNS. Together, these results reveal a previously undetermined mechanism through which NKX2.2 directs disparate transcriptional programs in the pancreas versus neuroepithelium.

Ghrelin is dispensable for embryonic pancreatic islet development and differentiation.

Ghrelin is a peptide hormone that has been implicated in the regulation of food intake and energy homeostasis. Ghrelin is predominantly produced in the stomach, but is also expressed in many other tissues where its functions are not well characterized. In the rodent and human pancreas, ghrelin levels peak at late gestation and gradually decline postnatally. Several studies have suggested that ghrelin regulates beta cell function during embryonic development and in the adult. In addition, in a number of mouse models, ghrelin cells appear to replace insulin- and glucagon-producing cells in the islet. In this analysis, we investigated whether the absence or overexpression of ghrelin influenced the development and differentiation of the pancreatic islet during embryonic development. These studies revealed that ghrelin is dispensable for normal pancreas development during gestation. Conversely, we demonstrated that elevated ghrelin in the Nkx2.2 null islets is not responsible for the absence of insulin- and glucagon-producing cells. Finally, we have also determined that in the absence of insulin, ghrelin cells form in their normal numbers and ghrelin is expressed at wild type levels.

Nkx2.2 regulates cell fate choice in the enteroendocrine cell lineages of the intestine.

Nkx2.2 is a homeodomain-containing transcription factor essential for pancreatic islet cell specification. In this study we investigate the role of Nkx2.2 within the small intestine. We have determined that Nkx2.2 is expressed at the onset of intestinal epithelial cell differentiation in specific intestinal cell populations, including a subset of enteroendocrine cells. Similar to its role in the pancreatic islet, Nkx2.2 regulates cell fate choices within the intestinal enteroendocrine population; in the Nkx2.2 null mice, several hormone-producing enteroendocrine cell populations are absent or reduced and the ghrelin-producing cell population is upregulated. The remaining intestinal cell populations, including the paneth cells, goblet cells, and enterocytes appear to be unaffected by the loss of Nkx2.2. Furthermore, similar to the pancreatic islet, Nkx2.2 appears to function upstream of Pax6 in regulating intestinal cell fates; Pax6 mRNA and protein expression is decreased in the Nkx2.2 null mice. These studies identify a novel role for Nkx2.2 in intestinal endocrine cell development and reveal the regulatory similarities between cell type specification in the pancreatic islet and in the enteroendocrine population of the intestine.

Sexual partner preference, hypothalamic morphology and aromatase in rams.

The male-oriented ram is a unique and valuable animal model for the study of hormonal, developmental and genetic contributions to sexual partner preference. Unlike most other mammalian models that are in use currently, variations in sexual attraction occur spontaneously in domestic ram populations. It is estimated that as many as 8-10% of rams exhibit a sexual partner preference for other males, classifying them as male-oriented rams. Studies have failed to identify any compelling social factors that can predict or explain the variations in sexual partner preferences of rams. Nor is there consensus on the endocrine and sensory responsiveness of male-oriented rams to other rams. However, a number of studies have reported differences in brain structure and function between male-oriented and female-oriented rams, suggesting that sexual partner preferences are neurologically hard-wired. Recently, we identified a sexually dimorphic nucleus (oSDN) in the sheep preoptic area-anterior hypothalamus. The oSDN is larger in female-oriented rams than in male-oriented rams and similar in size in male-oriented rams and ewes. In addition, mRNA levels for aromatase in the oSDN were higher in males than in females and were higher in female-oriented rams than in male-oriented rams. These results suggest a relationship between steroid hormones, specifically estrogens and oSDN morphology. In this review, we provide an overview of sexual behavior in rams and discuss the multiple factors that may contribute to the development and adult expression of same-sex partner preferences in rams.