RET Men2B -transgene Produces Sympathoadrenal Tumors But Does Not Prevent Intestinal Aganglionosis in gdnf −/− or gfrα-1 −/− Mice

Rajan, Indrani; Gestblom, Carolina; Kapur, Raj P.

doi:10.1007/s10024001-0039-9

Cited by 6 publications

(3 citation statements)

References 34 publications

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“…Approximately one half of the familial and one fifth of the sporadic mutations of Hirschsprung disease are associated with RET. Hirschsprung disease has been associated with multiple endocrine neoplasia types 2A and 2B, familial medullary thyroid carcinoma, and the Waardenburg‐Shah syndrome (hypopigmentation and cochlear neurosensory deafness) (23‐25). Currently, the only therapy available for affected individuals is resection of the aganglionic intestine.…”

Section: Introduction and General Concepts On The Enteric Nervous Systemmentioning

confidence: 99%

Enteric Nervous System Disease and Recovery, Plasticity, and Regeneration

Belkind‐Gerson¹,

Graeme‐Cook²,

Winter³

2006

J. pediatr. gastroenterol. nutr.

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Section: Introduction and General Concepts On The Enteric Nervous Systemmentioning

confidence: 99%

Enteric Nervous System Disease and Recovery, Plasticity, and Regeneration

Belkind‐Gerson¹,

Graeme‐Cook²,

Winter³

2006

J. pediatr. gastroenterol. nutr.

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“…Most MEN2A and FMTC mutations affect cysteine residues in the extracellular cysteine-rich domain (exons 10 and 11). A common mutation found in over 80% of typical MEN2A patients is a missense mutation at amino acid 634, particularly C634R, whereas FMTC/MEN2A mutations are spread among the various cysteine molecules of this region [ 58 , 59 ]. Patients with sporadic MTC also harbour somatic RET mutations in around 50% of cases, primarily at codons 768, 804, and 918.…”

Section: Men2 Syndromementioning

confidence: 99%

Familial syndromes associated with neuroendocrine tumours

Gut¹,

Komarowska²,

Czarnywojtek³

et al. 2015

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Neuroendocrine tumours may be associated with familial syndromes. At least eight inherited syndromes predisposing to endocrine neoplasia have been identified. Two of these are considered to be major factors predisposing to benign and malignant endocrine tumours, designated multiple endocrine neoplasia type 1 and type 2 (MEN1 and MEN2). Five other autosomal dominant diseases show more heterogeneous clinical patterns, such as the Carney complex, hyperparathyroidism-jaw tumour syndrome, Von Hippel-Lindau syndrome (VHL), neurofibromatosis type 1 (NF1) and tuberous sclerosis. The molecular and cellular interactions underlying the development of most endocrine cells and related organs represent one of the more complex pathways not yet to be deciphered. Almost all endocrine cells are derived from the endoderm and neuroectoderm. It is suggested that within the first few weeks of human development there are complex interactions between, firstly, the major genes involved in the initiation of progenitor-cell differentiation, secondly, factors secreted by the surrounding mesenchyme, and thirdly, a series of genes controlling cell differentiation, proliferation and migration. Together these represent a formula for the harmonious development of endocrine glands and tissue.

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“…To answer this question, one must consider what previous studies have shown: 1) expression of physiological levels of human Ret with the MEN 2B mutation in mice will not induce tumor formation (MTC, pheochromocytoma, or intestinal ganglioneuromas); 2) expression of physiological levels of murine Ret with the MEN 2B mutation in mice will induce C-cell hyperplasia, pheochromocytomas, and certain ganglioneuromas, but not MTC; 24 and 3) expression of supraphysiological levels of human Ret with the MEN 2B mutation (or the MEN 2A mutation) in mice will induce MTC and other associated tumors. [53][54][55][56][57] It seems possible that intrinsic differences in the human and mouse RET proteins exist such that oncogenic signals from physiological levels of mutant human RET in a mouse are insufficient to drive tumor formation (and that this insufficiency can be overcome by overexpressing mutant human RET). Alternatively, modifier genes may exist that must also be expressed in addition to activated Ret for the development of MTC and that this requirement for modifier genes can be overcome by overexpressing mutant human RET.…”

Section: Discussionmentioning

confidence: 99%

A Human Yeast Artificial Chromosome Containing the Multiple Endocrine Neoplasia Type 2B Ret Mutation Does Not Induce Medullary Thyroid Carcinoma but Does Support the Growth of Kidneys and Partially Rescues Enteric Nervous System Development in Ret-Deficient Mice

Skinner

Kalyanaraman

Safford

et al. 2005

The American Journal of Pathology

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We generated a line of transgenic mice using a yeast artificial chromosome containing the Ret mutation responsible for the multiple endocrine neoplasia type 2B syndrome (MEN 2B). The resulting animals did not develop any of the expected neoplasms associated with MEN 2B. Transgenic animals were then bred with animals lacking murine Ret (Ret M ) to further evaluate the function of human mutated Ret (Ret H 2B ) in the murine context. Whereas mice lacking Ret M exhibit intestinal aganglionosis and the absence of kidneys with other genitourinary anomalies, expression of the Ret H 2B transgene in Ret M -deficient mice allowed significant renal development with a partial rescue of the enteric nervous system. These Ret H 2B -positive/Ret M -deficient mice exhibit normal Ret expression and survive longer than Ret M -deficient mice, but still die at 3 to 5 days of age with evidence of enterocolitis. We conclude that the normal expression of a human Ret proto-oncogene with the MEN 2B mutation does not cause any features of MEN 2B in The Ret proto-oncogene encodes a receptor tyrosine kinase that regulates the growth and development within the neurological and excretory systems.1-3 The gene was discovered using the NIH3T3 transfection assay and the name Ret derives from this discovery (rearranged during transfection). 4 More recently, it was discovered that certain germ line mutations in the Ret proto-oncogene are associated with the multiple endocrine neoplasia (MEN) syndromes types 2A and 2B and familial medullary thyroid carcinoma (FMTC).5-9 These syndromes are inherited in an autosomal dominant manner. Patients with MEN 2A develop medullary thyroid carcinomas (MTCs), pheochromocytomas, and hyperparathyroidism; similarly, those with MEN 2B also develop MTCs and pheochromocytomas, but additionally develop mucosal neuromas of the lips, oral mucosa, and alimentary tract. Finally, FMTC is characterized only by the development of medullary thyroid carcinoma. 10 -12 To study the normal function of murine Ret (designated Ret M ), transgenic mice were created that lacked either Ret, the co-receptor GFR-␣1, or glial cell line-derived neurotrophic factor (GDNF), the cognate ligand for the receptor complex. [13][14][15][16][17][18] The Ret, GFR-␣1, and GDNF 18 The absence of intestinal ganglion cells is reminiscent of Hirschsprung's disease in humans, in which there is the congenital absence of enteric ganglia in the distal gut. Indeed, inactivating Ret mutations are also the most common defined cause of Hirschsprung's disease in humans. The importance of Ret in the development of the nervous system was further demonstrated when the other Ret ligands persephin, artemin, and neuturin were characterized and demonstrated to interact with Ret to support the growth of neurons in the peripheral, central, and enteric nervous systems (ENSs). 19 -23 Recently, to study the dominant transforming activity of the MEN 2B mutation of Ret, investigators created a transgenic mouse line containing the equivalent codon 918 Met to Thr mutation i...

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RET Men2B -transgene Produces Sympathoadrenal Tumors But Does Not Prevent Intestinal Aganglionosis in gdnf −/− or gfrα-1 −/− Mice

Cited by 6 publications

References 34 publications

Enteric Nervous System Disease and Recovery, Plasticity, and Regeneration

Enteric Nervous System Disease and Recovery, Plasticity, and Regeneration

Familial syndromes associated with neuroendocrine tumours

A Human Yeast Artificial Chromosome Containing the Multiple Endocrine Neoplasia Type 2B Ret Mutation Does Not Induce Medullary Thyroid Carcinoma but Does Support the Growth of Kidneys and Partially Rescues Enteric Nervous System Development in Ret-Deficient Mice

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