Members of the vertebrate hedgehog family (Sonic, Indian, and Desert) have been shown to be essential for the development of various organ systems, including neural, somite, limb, skeletal, and for male gonad morphogenesis. Sonic hedgehog and its cognate receptor Patched are expressed in the epithelial and/or mesenchymal cell components of the hair follicle. Recent studies have demonstrated an essential role for this pathway in hair development in the skin of Sonic hedgehog null embryos. We have further explored the role of the hedgehog pathway using anti-hedgehog blocking monoclonal antibodies to treat pregnant mice at different stages of gestation and have generated viable offspring that lack body coat hair. Histologic analysis revealed the presence of ectodermal placode and primodium of dermal papilla in these mice, yet the subsequent hair shaft formation was inhibited. In contrast, the vibrissae (whisker) development appears to be unaffected upon anti-hedgehog blocking monoclonal antibody treatment. Strikingly, inhibition of body coat hair morphogenesis also was observed in mice treated postnatally with anti-hedgehog monoclonal antibody during the growing (anagen) phase of the hair cycle. The hairless phenotype was reversible upon suspension of monoclonal antibody treatment. Taken together, our results underscore a direct role of the Sonic hedgehog signaling pathway in embryonic hair follicle development as well as in subsequent hair cycles in young and adult mice. Our system of generating an inducible and reversible hairless phenotype by anti-hedgehog monoclonal antibody treatment will be valuable for studying the regulation and mechanism of hair regeneration.
Expression of nestin has been suggested to be a characteristic of pancreatic islet stem cells. To determine whether nestin is indeed expressed in such putative cells during embryonic development, or in the adult pancreas after injury, we performed a cell lineage analysis using two independent lines of transgenic mice encoding Cre recombinase under the control of rat nestin cis-regulatory sequences, each crossed with loxP-bearing R26R mice. F1 animals produced the reporter molecule beta-galactosidase only upon Cre-mediated recombination, thus solely in cells using (or having used) the transgenic nestin promoter. In early pancreatic primordia, beta-galactosidase was observed in mesenchymal and epithelial cells. At later developmental stages or in adults, vast clusters of acinar cells and few ductal cells were labeled, in addition to fibroblasts and vascular cells, but no endocrine cells were tagged by beta-galactosidase. This correlated with the transient expression, observed with an anti-nestin antibody, of endogenous nestin in about 5% of epithelial cells during development (whether in cord-forming arrangements or in nascent acini), and in vascular and mesenchymal structures. After partial pancreatectomy, there was a transient increase of the number of anti-nestin-labeled endothelial cells, but again, no endocrine cells bore beta-galactosidase. Together, these findings show that nestin is expressed in the pancreatic exocrine cell lineage, and suggest that consistent nestin expression is not a major feature of islet endocrine progenitor cells.
Pancreas Differentiation and MorphogenesisThe pancreas contains endocrine and exocrine cells. The exocrine pancreas represents more than 95% of the gland; it is composed of the acinar secretory cells, producing digestive enzymes such as amylase, and the excretory ducts. The endocrine cells of the pancreas form clusters embedded in the exocrine tissue: the islets of Langerhans. Islets are composed of four types of endocrine cells: the centrally located b cells produce insulin, while the peripheral a, d, and PP cells produce glucagon, somatostatin, and pancreatic polypeptide, respectively. Pancreas OrganogenesisThe pancreas initially develops from distinct dorsal and ventral primordia that later fuse to form the mature organ. This involves a sequential cascade of inductive events in association with the activation of specific transcription factors. Pancreatic buds evaginate from the early foregut endoderm caudally to the stomach primordium, near the prospective liver: the molecular determinants that define the position of the pancreas along the anterior-posterior axis remain unknown (1,2). The first hormone-containing cells found in early primordia are epithelial and appear located exclusively within the walls of the embryonic ducts or cords. Contrary to what is observed in adult islets, these cells frequently contain simultaneously more than one hormone; this has suggested the existence of a common precursor cell for all four islet cell types. For instance, because glucagon-containing cells are the first to differentiate in early buds, and given the presence of cells co-expressing glucagon and insulin, it was proposed that mature insulin cells derive from glucagon progenitors (3).Commitment to a pancreatic fate occurs as early as embryonic d 8-8.5 (E8-E8.5) in mice. Permissive signals released from adjacent mesodermal structures, including the notochord, aorta, and cardiac mesoderm, are important for induction of the pancreatic program. The notochord induces dorsal pancreas development through the inhibition of SHH (Sonic hedgehog) in pre-pancreatic dorsal endoderm. Shh is expressed in the early gut endoderm and has been shown to pattern it (1,(4)(5)(6). This Shh repression, which appears to be by activin bB and FGF2 (7), is permissive for the expression of Pdx1. Shh is also repressed, and Pdx1 expressed, in the ventral pre-pancreatic endoderm.It is intriguing that the same mesenchymal morphogens have opposite inductive effects on the dorsal and ventral pancreas: in the absence of dorsal mesoderm, the dorsal endoderm expresses liver markers, whereas, without ventral mesoderm (i.e., cardiac mesoderm and septum transversum), the ventral endoderm "defaults" to pancreas instead of liver. Indeed, signals from ventral mesoderm (FGFs) promote hepatic development (8).The first indication of morphogenesis occurs at E9.5, when the dorsal mesenchyme condenses and the underlying endoderm evaginates to form a recognizable dorsal pancreatic bud; the ventral bud appears one day later (E10.5). Both buds subsequently proliferate,...
Mice bearing a Cre-encoding transgene driven by a compound [SV40 small t antigen/mousealpha-amylase-2] promoter expressed the recombinase at early developmental stages broadly in the embryonic endoderm before the pancreas and lungs begin to outgrow, but not in other germ layers, as determined indirectly by beta-galactosidase and YFP reporter activity, indicating that the transgene is in fact an endodermic marker. Interestingly, the liver and ventral pancreas were excluded from this expression pattern, denoting that the chimerical alpha-amylase-2 promoter was not active in the anterior leading edge of the endoderm (the presumptive region from which liver and ventral pancreas form). These transgenics thus confirm, among other findings, that dorsal and ventral pancreatic primordia have different intrinsic transcriptional capabilities. In conclusion, we have generated a new transgenic mouse that should be useful to target endoderm at early stages, without affecting the liver or ventral pancreas before embryonic day E12.5.
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