Background & Aims: Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of the enteric nervous system (ENS). HSCR potentially involves multiple gene aberrations and displays complex patterns of inheritance. Mutations of the RET gene, encoding the RET receptor tyrosine kinase, play a central role in the pathogenesis of HSCR.
View Article and Find Full Text PDFEnteroendocrine cells (EECs) are the primary sensory cells that sense the gut luminal environment and secret hormones to regulate organ function. Recent studies revealed that vagal afferent neurons are connected to EECs and relay sensory information from EECs to the brain stem. To date, however, the identity of vagal afferent neurons connected to a given EEC subtype and the mode of their gene responses to its intestinal hormone have remained unknown.
View Article and Find Full Text PDFHirschsprung disease (HSCR) is characterized by congenital absence of enteric neurons in distal portions of the gut. Although recent studies identified Schwann cell precursors (SCPs) as a novel cellular source of enteric neurons, it is unknown how SCPs contribute to the disease phenotype of HSCR. Using Schwann cell-specific genetic labeling, we investigated SCP-derived neurogenesis in two mouse models of HSCR; Sox10 haploinsufficient mice exhibiting distal colonic aganglionosis and Ednrb knockout mice showing small intestinal aganglionosis.
View Article and Find Full Text PDFMutations of the gene encoding the tyrosine kinase causes Hirschsprung's disease (HSCR) and medullary thyroid carcinoma (MTC). Current consensus holds that HSCR and MTC are induced by inactivating and activating RET mutations, respectively. However, it remains unknown whether activating mutations in the gene have adverse effects on ENS development We addressed this issue by examining mice engineered to express RET51(C618F), an activating mutation identified in MTC patients.
View Article and Find Full Text PDFMissense mutations of the RET gene have been identified in both multiple endocrine neoplasia (MEN) type 2A/B and Hirschsprung disease (HSCR: congenital absence of the enteric nervous system, ENS). Current consensus holds that MEN2A/B and HSCR are caused by activating and inactivating RET mutations, respectively. However, the biological significance of RET missense mutations in vivo has not been fully elucidated.
View Article and Find Full Text PDFMedullary thyroid carcinoma (MTC) develops from hyperplasia of thyroid C cells and represents one of the major causes of thyroid cancer mortality. Mutations in the cysteine-rich domain (CRD) of the RET gene are the most prevalent genetic cause of MTC. The current consensus holds that such cysteine mutations cause ligand-independent dimerization and constitutive activation of RET.
View Article and Find Full Text PDFThe gastrointestinal (GI) tract is innervated by intrinsic enteric neurons and by extrinsic efferent and afferent nerves. The enteric (intrinsic) nervous system (ENS) in most regions of the gut consists of two main ganglionated layers; myenteric and submucosal ganglia, containing numerous types of enteric neurons and glial cells. Axons arising from the ENS and from extrinsic neurons innervate most layers of the gut wall and regulate many gut functions.
View Article and Find Full Text PDFUnlabelled: Elucidation of the cellular identity of neuronal precursors provides mechanistic insights into the development and pathophysiology of the nervous system. In the enteric nervous system (ENS), neurogenesis persists from midgestation to the postnatal period. Cellular mechanism underlying the long-term neurogenesis in the ENS has remained unclear.
View Article and Find Full Text PDFPleiotropic growth factors play a number of critical roles in continuous processes of embryonic development; however, the mechanisms by which a single regulatory factor is able to orchestrate diverse developmental events remain imperfectly understood. In the development of the enteric nervous system (ENS), myenteric ganglia (MGs) form initially, after which the submucosal ganglia (SMGs) develop by radial inward migration of immature ENS precursors from the myenteric layer. Here, we demonstrate that glial cell line-derived neurotrophic factor (GDNF) is essential for the formation not only of the MGs, but the SMGs as well, establishing GDNF as a long-term acting neurotrophic factor for ENS development in a mouse model.
View Article and Find Full Text PDFThe most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB.
View Article and Find Full Text PDFCell migration is fundamental to organogenesis. During development, the enteric neural crest cells (ENCCs) that give rise to the enteric nervous system (ENS) migrate and colonize the entire length of the gut, which undergoes substantial growth and morphological rearrangement. How ENCCs adapt to such changes during migration, however, is not fully understood.
View Article and Find Full Text PDFThe RET tyrosine kinase is required for the migration, proliferation, and survival of the enteric neural crest-derived cells (ENCCs) that form the enteric nervous system (ENS). Hypomorphic RET alleles cause intestinal aganglionosis [Hirschsprung disease (HSCR)], in which delayed migration and successive nonapoptotic ENCC death are considered to be major contributory factors. The significance of ENCC death in intestinal aganglionosis, however, has remained unclear.
View Article and Find Full Text PDFMutations in the RET gene are the primary cause of Hirschsprung disease (HSCR), or congenital intestinal aganglionosis. However, how RET malfunction leads to HSCR is not known. It has recently been shown that glial cell line-derived neurotrophic factor (GDNF) family receptor alpha1 (GFRalpha1), which binds to GDNF and activates RET, is essential for the survival of enteric neurons.
View Article and Find Full Text PDFThe regulation of neuronal survival and death by neurotrophic factors plays a central role in the sculpting of the nervous system, but the identity of survival signals for developing enteric neurons remains obscure. We demonstrate here that conditional ablation of GFRalpha1, the high affinity receptor for GDNF, in mice during late gestation induces rapid and widespread neuronal death in the colon, leading to colon aganglionosis reminiscent of Hirschsprung's disease. Enteric neuron death induced by GFRalpha1 inactivation is not associated with the activation of common cell death executors, caspase-3 or -7, and lacks the morphological hallmarks of apoptosis, such as chromatin compaction and mitochondrial pathology.
View Article and Find Full Text PDFEnteric nervous system (ENS) development requires complex interactions between migrating neural-crest-derived cells and the intestinal microenvironment. Although some molecules influencing ENS development are known, many aspects remain poorly understood. To identify additional molecules critical for ENS development, we used DNA microarray, quantitative real-time PCR and in situ hybridization to compare gene expression in E14 and P0 aganglionic or wild type mouse intestine.
View Article and Find Full Text PDFRegulatory protein kinases are involved in various cellular processes such as proliferation, differentiation, and apoptosis. Using cDNA differential display, we identified MOK, a member of the mitogen-activated protein kinase superfamily, as one of the genes induced by a caudal-related homeobox transcription factor, Cdx2. Analysis of the 5'-flanking region of the MOK gene led to the identification of primary Cdx2 responsive element, and an electrophoretic mobility shift assay indicated that Cdx2 binds to that element.
View Article and Find Full Text PDFThe caudal-related homeobox transcription factor (Cdx2) plays an important role in intestinal development, differentiation, and homeostasis. However, only a limited number of Cdx2-regulated target genes have been elucidated. To delineate the molecular mechanism regulated downstream of Cdx2, we aimed to define Cdx2-regulated genes.
View Article and Find Full Text PDFHiroshima J Med Sci
September 2003
Tritiated water at 23.2, 46.3 or 92.
View Article and Find Full Text PDFThe present study was designed to investigate the protective effect of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (designated as MAK) on the induction and development of azoxymethane (AOM)-induced colon tumors in male F344/Du Crj rats. A total of 80 animals were divided into five groups at six weeks of age, groups 2, 3 and 4 being given weekly subcutaneous injections of AOM (15 mg/kg body weight) for the initial 3 weeks to induce colon tumors. Rats in group 1 and 5 were injected with the vehicle, 0.
View Article and Find Full Text PDFIn this experiment, methylnitrosourea (MNU) was administered, followed by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), to assess effects of surrogate mothering on tumor. One or two day old male SD pups were treated with or without 30 mg/kg body weight of MNU and nursed by SD or ACI surrogate mothers for 5 weeks. When 6-weeks-old they were then treated with 100 ppm MNNG or tap water for 16 weeks.
View Article and Find Full Text PDFAm J Physiol Gastrointest Liver Physiol
October 2002
Development and differentiation of the intestinal epithelium appear to be regulated by various growth factors. Using cDNA microarrays, we identified heparin-binding EGF-like growth factor (HB-EGF) as one of the genes induced by intestinal-specific transcription factor Cdx2 in an intestinal undifferentiated rat cell line, intestinal epithelial cell (IEC)-6. Both Cdx2 and HB-EGF stimulated cell proliferation and migration, and their effects were inhibited partially by an EGF receptor-specific tyrosine kinase inhibitor, PD-153035.
View Article and Find Full Text PDFThe present study was designed to investigate the effects of fermented miso in the diet on the induction of gastric tumors by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in male CD (SD) rats. A total of 120 animals, 6 weeks of age, were divided into 6 groups and given MNNG (100 ppm) in the drinking water for 16 weeks. Starting 1 week before the carcinogen treatment the rats were fed a normal control MF solid diet, or the same diet containing 10% long-term fermented, medium- or short-term fermented miso, or 1% NaCl until the end of the MNNG exposure period.
View Article and Find Full Text PDFWe evaluated the level of MCL1 gene expression using quantitative reverse transcription polymerase chain reaction in lymph nodes of patients with non-Hodgkin lymphoma (NHL). MCL1 expression in patients in complete remission (CR) was significantly lower than in patients with progressive disease (PD, P = 0.0043).
View Article and Find Full Text PDFThe protective effects of a dietary water-soluble extract from cultured medium of Ganoderma lucidum (Rei-shi or Mannentake) mycelia (designated as MAK) against development of colon tumors were investigated in male ICR mice. The animals were given weekly injections of N,N'-dimethylhydrazine (DMH, 10 mg/kg body weight) for the initial 10 weeks to induce colon carcinogenesis, and then fed on diet with or without 5% MAK for 10 weeks. There were no significant differences in incidence and the total number of colon tumors between the groups.
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