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

Chacchu Bhattarai; Phanindra Prasad Poudel; Arnab Ghosh; Sneha Guruprasad Kalthur

doi:10.3934/Neuroscience.2022008

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

AIMS Neurosci. 2022 Mar 16;9(1):128-149. doi: 10.3934/Neuroscience.2022008. eCollection 2022.

Authors

Chacchu Bhattarai^{1

2}, Phanindra Prasad Poudel^{1

2}, Arnab Ghosh³, Sneha Guruprasad Kalthur¹

Affiliations

¹ Department of Anatomy, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Karnataka, 576104, India.
² Department of Anatomy, Manipal College of Medical Sciences, Pokhara, Nepal.
³ Department of Pathology, Manipal College of Medical Sciences, Pokhara, Nepal.

Abstract

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 (RET) gene and its protein RET plays a crucial role in the formation of enteric neurons. This review describes the molecular mechanism by which the RET 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 RET gene result in Hirschsprung's disease.

Keywords: Hirschsprung's disease; RET gene; enteric neuron; gut wall; neurogenesis.

Publication types

Review