Lack of β1 integrins in enteric neural crest cells leads to a Hirschsprung-like phenotype

Abstract

The enteric nervous system arises mainly from vagal and sacral neural crest cells that colonise the gut between 9.5 and 14 days of development in mice. Using the Cre-LoxP system, we removed ␤1 integrins in the neural crest cells when they emerge from the neural tube. ␤1-null enteric neural crest cells fail to colonise the gut completely, leading to an aganglionosis of the descending colon, which resembles the human Hirschsprung's disease. Moreover, ␤1-null enteric neural crest cells form abnormal aggregates in the gut wall, leading to a severe alteration of the ganglia network organisation. Organotypic cultures of gut explants reveal that ␤1-null enteric neural crest cells show impaired adhesion on extracellular matrix and enhanced intercellular adhesion properties. They display migration defects in collagen gels and gut tissue environments. We also provide evidence that ␤1 integrins are required for the villi innervation in the small intestine. Our findings highlight the crucial roles played by ␤1 integrins at various steps of enteric nervous system development.

A Rap GTPase interactor, RADIL, mediates migration of neural crest precursors

“…Conditional deletion of ␤1 integrin by Ht-PA-Cre, expressed specifically in NC cells at the start of migration, leads to severe Hirschsprung-like phenotypes in mice (Breau et al 2006). Cadherin-11 in mouse and Xenopus and Cadherin-7 in chick are specifically expressed only in the migratory NC and not in the earlier premigratory NC.…”

Cell biology of embryonic migration

“…Reduced neural crest cell motility (Breau et al, 2006) β3 integrin Integrins Total Defects in platelet aggregation and clot retraction, hemmorhages, postnatal anemia, and reduced survival (Hodivala-Dilke, 1999) β8 integrin Integrins Total Embryonic or perinatal lethality with profound defects in vascular development, insufficient vascularization of the placenta and yolk sac (Zhu et al, 2002) VCAM-1 Integrins Total Embrynic lethality at E10-12, abnormal placental development (Gurtner et al, 1995) Syndecan-4 Extracellular matrix Total Blood vessel defects in the placenta; defects in angiogenesis and wound repair (Echtermeyer, 2001;Ishiguro, 2000;Kojima, 2002) N-syndecan Extracellular matrix Total Impaired neural migration in the developing brain (Hienola et al, 2006) Perlecan Extracellular matrix Total Defects in heart integrity, invasion of brain tissue into the overlaying ectoderm, severe defect in cartilage, cleft palates and death shortly after birth from respiratory failure. (Costell et al, 1999) Tenascin C Extracellular matrix Total NC cells fail to disperse laterally (Tucker, 2001) Laminin γ1 Extracellular matrix Total Death at E5.5, lack of basement membranes (Smyth et al, 1999) Laminin β2 Extracellular matrix Total Postnatal death between P15-30, neuromuscular junctions and glomerular defects (Noakes et al, 1995a;Noakes et al, 1995b;Patton et al, 1997) Laminin α2 Extracellular matrix Total Death by 5 weeks postnatal, severe muscular dystrophy and peripheral neurophathy (Miyagoe et al, 1997) Laminin α2 (dy/dy) Extracellular matrix Spontaneous Adult lethality, severe muscular dystrophy and peripheral nerve dysmyelination (Patton et al, 1999;Patton et al, 1997) Laminin α3 Extracellular matrix Total Death at P2-3, epithelial adhesion defect (Ryan et al, 1999) Laminin α4 Extracellular matrix Total Transient microvascular defect with hemorrhages and misalignment of neuromuscular junctions (Patton et al, 2001;Thyboll et al, 2002) Laminin α5 Extracellular matrix Total Death at E14-E17, with placental vessel, neural (Miner et al, 1998;Miner and Li, 2000) Protein Function Type Phenotype Reference tube, limb, and kidney defects Fibronectin Extracellular matrix Total Death before E14.5, shortened anterior-posterior axes, deformed neural tubes, and defects in mesodermally derived tissues.…”

Migration and differentiation of transplanted enteric neural crest-derived cells in murine model of Hirschsprung’s disease

“…Formation of group of neuronal cell bodies, called ganglia is a characteristic feature of ENS. b1-integrin and BMPsignaling have been implicated in ganglion formation during development of the ENS as depletion of b1-integrin or perturbations in BMP-signaling result in a failure of enteric neural crest cells to cluster properly and form normal shaped and sized ganglia (Goldstein et al 2005;Fu et al 2006;Breau et al 2006). Although it is implicated that even aganglionic gut may contain environmental cue or molecules supporting transplanted enteric neuronal stem/progenitor cells to form ganglia-like cell clusters (Hotta et al 2013), its underlying mechanism is not clearly understood.…”