A central challenge in embryonic development is to understand how growth and pattern are coordinated to direct emerging new territories during morphogenesis. Here, we report on a signaling cascade that links cell proliferation and fate, promoting formation of a distinct progenitor domain within the developing chick hypothalamus. We show that the downregulation of Shh in floor plate-like cells in the forebrain governs their progression to a distinctive, proliferating hypothalamic progenitor domain. Shh downregulation occurs via a local BMP-Tbx2 pathway, Tbx2 acting to repress Shh expression. We show in vivo and in vitro that forced maintenance of Shh in hypothalamic progenitors prevents their normal morphogenesis, leading to maintenance of the Shh receptor, ptc, and preventing progression to an Emx2(+)-proliferative progenitor state. Our data identify a molecular pathway for the downregulation of Shh via a BMP-Tbx2 pathway and provide a mechanism for expansion of a discrete progenitor domain within the developing forebrain.

SUMMARYThe infundibulum links the nervous and endocrine systems, serving as a crucial integrating centre for body homeostasis. Here we describe that the chick infundibulum derives from two subsets of anterior ventral midline cells. One set remains at the ventral midline and forms the posterior-ventral infundibulum. A second set migrates laterally, forming a collar around the midline. We show that collar cells are composed of Fgf3 + SOX3 + proliferating progenitors, the induction of which is SHH dependent, but the maintenance of which requires FGF signalling. Collar cells proliferate late into embryogenesis, can generate neurospheres that passage extensively, and differentiate to distinct fates, including hypothalamic neuronal fates and Fgf10 + anterior-dorsal infundibular cells. Together, our study shows that a subset of anterior floor plate-like cells gives rise to Fgf3 + SOX3 + progenitor cells, demonstrates a dual origin of infundibular cells and reveals a crucial role for FGF signalling in governing extended infundibular growth.

As bstract. Naturally occurring derivatives of pro-opiomelanocortin (POMC) have been identified in various extra-pituitary sites, including the endocrine and exocrine pancreas. Corticotropin-like intermediate lobe peptide (CLIP=ACTH18-39), a naturally occurring derivative of POMC, has been suggested to be an insulin secretagogue. To determine whether CLIP might also affect the exocrine pancreas, we measured its effect on amylase secretion and protein synthesis dnd secretion in isolated rat pancreatic lobules. Lobules were dual-pulsed with trace amounts of '4C-and 3H-leucine, both in the presence and absence of CLIP (10-9_10-6 M), using a technique that permitted the labeling of both the synthetic and secretory compartments.

Rat pancreatic lobules were used to investigate the interaction of gastric inhibitory polypeptide (GIP), carbachol, glucose, and an amino acid mixture on insulin secretion. At 5 mM glucose, GIP (1.1 ng/ml) did not augment insulin secretion in the presence or absence of carbachol (5 X 10(-5)M) during a 210-min incubation. However, at 11 mM glucose, GIP did augment insulin secretion in the presence (342.5 +/- 62.0 vs. 212.5 +/- 50.5 microU . ml-1 . mg tissue-1, mean +/- SE; P less than 0.01) but not the absence (217.0 +/- 45.5 vs. 205.8 +/- 35.0 microU . ml-1 . mg tissue-1) of carbachol. During subsequent 30-min incubations, GIP was increased to a supra-physiological concentration of 11 ng/ml and again augmented insulin secretion with (65.8 +/- 10.8 vs. 27.8 +/- 2.4 microU . ml-1 . mg tissue-1 . h-1; P less than 0.001) but not without (37.2 +/- 1.8 vs. 30.2 +/- 2 microU . ml-1 . mg-1 tissue-1 . h-1) carbachol present. This GIP-mediated insulin secretion was blocked by atropine (34.8 to 1.8 vs. 37.6 +/- 1.6 microU . ml-1 . mg tissue-1 . h-1). At amino acid concentrations of 21 and 211 mM, but not 2.1 mM, GIP augmented insulin release but again only with carbachol present. In conclusion, porcine GIP augments amino acid as well as glucose-mediated insulin secretion in vitro. Furthermore, this biological action is dependent on an, as yet, unidentified cholinergic mechanism. The pathophysiological significance of the neural-hormonal interaction deserves further investigation.