Development of the interstitial cell of cajal: Origin, kit dependence and neuronal and nonneuronal sources of kit ligand

Kit is a marker for interstitial cells of Cajal (ICC). ICCs interact with e nteric neurons and are essential for gastrointestinal motility. The roles o f neural crest-derived cells, neurons, Kit, and Kit ligand (KL) in ICC deve lopment were analyzed. ICC development lagged behind that of neurons and sm ooth muscle;although mRNA encoding Kit and KL was detected at Ell, Kit-immu noreactive ICCs did not appear until E12 in foregut and E14 in terminal hin dgut. Transcripts of Kit and KL and Kit-immunoreactive cells were found in aganglionic gut from Is/Is and c-ret -/- mice. ICCs also developed in crest -free cultures of Is/Is terminal colon. ICCs appeared in cultures of noncre st- but not those of crest-derived cells isolated from the fetal bowel by i mmunoselection with antibodies to p75(NTR). KL immunoreactivity was coincid ent in cells with neuronal or smooth muscle markers. The development of ICC s in cultures of mixed cells dissociated from the fetal gut was dependent o n plating density. No ICCs appeared at less than or equal to 80,000 cells/m l, but many cells, including filamentous ICCs, appeared at greater than or equal to 200,000 cells/ml. Exogenous KL partially substituted for a high pl ating density. These data support the ideas that mammalian ICCs are neither derived from the neural crest nor developmentally dependent on neurons. IC C differentiation/survival requires KL, which can be provided by neurons or cells in a smooth muscle lineage. Neurons may be needed for development of myenteric ICCs and the mature ICC network. (C) 2000 Wiley-Liss, Inc.