Specific inactivation of TGF signaling in neural crest stem cells (NCSCs) results in cardiovascular defects and thymic, parathyroid, and craniofacial anomalies. All these malformations characterize DiGeorge syndrome, the most common microdeletion syndrome in humans. Consistent with a role of TGF in promoting non-neural lineages in NCSCs, mutant neural crest cells migrate into the pharyngeal apparatus but are unable to acquire non-neural cell fates. Moreover, in neural crest cells, TGF signaling is both sufficient and required for phosphorylation of CrkL, a signal adaptor protein implicated in the development of DiGeorge syndrome. Thus, TGF signal modulation in neural crest differentiation might play a crucial role in the etiology of DiGeorge syndrome.Supplemental material is available at http://www.genesdev.org.Received July 16, 2004; revised version accepted December 23, 2004. During development, neural crest cells emerge from the dorsal part of the neural tube and emigrate to various locations within the embryo to generate most of the peripheral nervous system and a variety of other structures (Le Douarin and Dupin 2003). In particular, neural crest cells localized in the pharyngeal apparatus contribute to non-neural tissues, such as craniofacial bone and cartilage, thymus, parathyroid glands, and cardiac outflow tract and septum (Kirby and Waldo 1995;Jiang et al. 2000;Graham 2003). The function of neural crest cells in the generation of these tissues, however, has been debated (Graham 2003).Formation of the pharyngeal apparatus involves complex interactions of neural crest, ectoderm, endoderm, and mesoderm whose development must be coordinated (Graham 2003). Significantly, alterations to the development of this region are often associated with congenital human birth defects such as DiGeorge or Velocardiofacial syndrome. DiGeorge syndrome is the most common microdeletion syndrome in humans, characterized by cardiovascular defects plus thymic, parathyroid, and craniofacial anomalies (Lindsay 2001;Vitelli and Baldini 2003). Approximately 80% of the patients carry a variably sized deletion on chromosome 22 (del22q11). Ablation of genes affected by the microdeletion indicated two pathophysiological mechanisms causing DiGeorge syndrome: Mutations of the transcription factor Tbx1 lead to disturbed pharyngeal arch patterning. Consequently, neural crest cells are unable to populate the pharyngeal apparatus ( Previously, cell culture experiments allowed the identification of several growth factors able to instruct migratory and post-migratory neural crest cells to adopt specific lineages (Le Douarin and Dupin 2003;Lee et al. 2004). One of these factors is transforming growth factor (TGF) , which elicits multiple responses in cultured neural crest stem cells (NCSCs). Depending on the cellular context, it can promote the generation of non-neural smooth-muscle-like cells or autonomic neurons, or induce apoptosis (Shah et al. 1996;Hagedorn et al. 1999Hagedorn et al. , 2000. Here we investigated the role of TGF si...
Regulating the choice between neural stem cell maintenance versus differentiation determines growth and size of the developing brain. Here we identify TGF-beta signaling as a crucial factor controlling these processes. At early developmental stages, TGF-beta signal activity is localized close to the ventricular surface of the neuroepithelium. In the midbrain, but not in the forebrain, Tgfbr2 ablation results in ectopic expression of Wnt1/beta-catenin and FGF8, activation of Wnt target genes, and increased proliferation and horizontal expansion of neuroepithelial cells due to shortened cell-cycle length and decreased cell-cycle exit. Consistent with this phenotype, self-renewal of mutant neuroepithelial stem cells is enhanced in the presence of FGF and requires Wnt signaling. Moreover, TGF-beta signal activation counteracts Wnt-induced proliferation of midbrain neuroepithelial cells. Thus, TGF-beta signaling controls the size of a specific brain area, the dorsal midbrain, by antagonizing canonical Wnt signaling and negatively regulating self-renewal of neuroepithelial stem cells.
Calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin are structurally related peptides with N-terminal 6-7 amino acid ring structures linked by a disulfide bridge and with amidated C-termini. Among the related bioactive peptides, the structures of the calcitonin receptor and subtypes thereof have been identified so far through molecular cloning. Cross-reaction between receptors of calcitonin, calcitonin gene-related peptide, adrenomedullin and amylin, as well as overlapping biological actions, anticipate that the respective receptors belong to a family of G-protein-coupled receptors that include those of parathyroid hormone, secretin and vasointestinal peptide.
Human receptor activity modifying proteins (RAMP) regulate the ligand specificity of the calcitonin-receptor-like-receptor (McLatchie et al., Nature 393:333-339 (1998)). Here we have investigated binding of [125I]-labeled human (h) calcitonin ([125I]hCT) and rat amylin ([125I]amylin) to rabbit aortic endothelial cells (RAEC) co-transfected with the hCT receptor isotype 2 (hCTR2) and RAMP1, -2 or -3. Specific binding of 125 pM [125I]hCT to cells transfected with hCTR2 alone was 6.7 +/- 0.7 fmol/50,000 cells (n=5), and was reduced by 45 +/- 2% and 86 +/- 3% (P < 0.001) in the presence of RAMP1 and -3, but remained unchanged with RAMP2. In the absence and presence of individual RAMPs [125I]hCT binding inhibition occured with similar IC50 of between 6 nM and 11 nM hCT, and human amylin was 24- to 54-fold less potent. Specific binding of 125 pM [125I]amylin to cells transfected with hCTR2 alone was 0.9 +/- 0.2 fmol/50,000 cells (n=6), and was increased by 262 +/- 48% (P < 0.005), 73 +/- 26% (P < 0.05) and 338 +/- 57% (P < 0.005) with RAMP1, -2 or -3, respectively. [125I]amylin binding was inhibited with IC50 of 3.1 +/- 0.5 nM and 4.0 +/- 0.8 nM human amylin in cells co-transfected with RAMP1 or -3, respectively, and hCT was 45 +/- 2- and 126 +/- 3-fold less potent. In conclusion, RAMP1 and -3 decrease calcitonin receptor expression in RAEC transfected with hCTR2 encoding cDNA and simultanously reveal an amylin receptor.
Immunoreactive calcitonin (CT), indistinguishable from human CT-(1-32) and its sulfoxide, has been identified in extracts of the hypothalamus, the pituitary, and the thyroid obtained from human subjects at autopsy. CT concentrations were highest in a region encompassing the posterior hypothalamus, the median eminence, and the pituitary; intermediate in the substantia nigra, the anterior hypothalamus, the globus pallidus, and the inferior colliculus; and low in the caudate nucleus, the hippocampus, the amygdala, and the cerebral and cerebellar cortices. Specific CT binding measured with "MI-labeled salmon CT was high-
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