The <i>RET</i> gene encodes RET protein, which triggers intracellular signaling pathways for enteric neurogenesis, and <i>RET</i> mutation results in Hirschsprung's disease

Abstract

&lt;abstract&gt; &lt;p&gt;Enteric neurons and ganglia are derived from vagal and sacral neural crest cells, which undergo migration from the neural tube to the gut wall. In the gut wall, they first undergo rostrocaudal migration followed by migration from the superficial to deep layers. After migration, they proliferate and differentiate into the enteric plexus. Expression of the Rearranged During Transfection (&lt;italic&gt;RET&lt;/italic&gt;) gene and its protein RET plays a crucial role in the formation of enteric neurons. This review describes the molecular mechanism by which the &lt;italic&gt;RET&lt;/italic&gt; gene and the RET protein influence the development of enteric neurons. Vagal neural crest cells give rise to enteric neurons and glia of the foregut and midgut while sacral neural crest cells give rise to neurons of the hindgut. Interaction of RET protein with its ligands (glial cell derived neurotrophic factor (GDNF), neurturin (NRTN), and artemin (ARTN)) and its co-receptors (GDNF receptor alpha proteins (GFRα1-4)) activates the Phosphoinositide-3-kinase-protein kinase B (PI3K-PKB/AKT), RAS mitogen-activated protein kinase (RAS/MAPK) and phospholipase Cγ (PLCγ) signaling pathways, which control the survival, migration, proliferation, differentiation, and maturation of the vagal and sacral neural crest cells into enteric neurons. Abnormalities of the &lt;italic&gt;RET&lt;/italic&gt; gene result in Hirschsprung's disease.&lt;/p&gt; &lt;/abstract&gt;

Association of rs2435357 and rs2506030 polymorphisms in RET with susceptibility to hirschsprung disease: A systematic review and meta-analysis

“…RET protein has three different subtypes, named RET51, RET43, and RET9. Moreover, Bhattarai et al ( 37 ) showed that interactions between RET protein and its ligands can control the survival, migration, proliferation, differentiation, and maturation of vagal and sacral neural crest cells. Nagy et al ( 38 ) demonstrated that excessive stimulation of RET al.…”

RET Proto-Oncogene—Not Such an Obvious Starting Point in Cancer Therapy

“…On the other hand, RET rearrangements are described in papillary thyroid carcinoma, non-small cell lung carcinoma, and other sporadic types of cancers. Gain of function aberrations are present mostly in oncogenic diseases, but RET may also be inactivated, causing Hirschsprung’s disease, congenital kidney or urinary tract anomalies, or innate central hypoventilation syndrome [ 13 , 14 ].…”

“…These are most commonly described in Hirschsprung’s disease (HSCR), a congenital malformation with the presence of aganglionosis of the gastrointestinal tract. RET mutations occur in approximately 50% of familial and 10–20% of sporadic cases of HSCR [ 14 , 49 , 50 , 51 ]. There are different mechanisms of RET impairment and consequently loss of its function, mainly depending on the localization of mutation.…”

Two sisters diagnosed with familial paraganglioma syndrome type 1 (FPGL1) and multiple endocrine neoplasia type 2A (MEN2A)

“…It’s inherited in an autosomal dominant manner and features medullary thyroid carcinoma, hyperparathyroidism, and pheochromocytoma [ 4 , 5 ]. The condition arises from a RET (rearranged during transfection variant) [ 6 ] gene variant on chromosome 10q11.2, which often results in medullary thyroid carcinoma, typically diagnosed before 35 years [ 7 – 9 ]. Pheochromocytoma, another manifestation of MEN2A, affects fewer than half of patients, yet bilateral pheochromocytoma in MEN2A is not uncommon, occurring in 50–80% of cases [ 10 , 11 ].…”