Action potential generation, Kit receptor immunohistochemistry and morphology of steel‐Dickie (Sl/Sl^d) mutant mouse small intestine

Abstract

In contrast to wild-type mice, homozygotes with mutations of the W locus do not express the functional Kit receptor and are severely deficient in the Auerbach's plexus (AP)-associated subtype of interstitial cells of Cajal (ICC-AP). With a morphologically intact neural and muscular structure, the absence in these mutants of both small-intestinal slow waves and ICC-AP constitutes strong evidence for a key role of ICC-AP as pacemaker cells. In steel-Dickie mutant mice (Sl/Sld), the gene coding for the Kit ligand (stem cell factor) is defective. We examined Sl/Sld mutants and controls with intracellular microelectrode techniques, combined with light and electron microscopy. The absence of the normal Kit ligand (Sl/Sld mice) had very similar effects as the absence of the Kit receptor in viable mice, mutated at the White spotting, W, locus (W/Wv mice), in that neither slow waves, nor Kit receptor immunoreactivity in the region of Auerbach's plexus nor ICC-AP were present in the small intestine. In the Sl/Sld mouse, the smooth muscle cells generated action potentials at variable frequencies from a depolarized cell membrane of -40 to -55 mV. Increasing excitability by K channel blockers created many different patterns of action potential generation and the frequency increased from approximately 16 cpm to 66 cpm. This was in sharp contrast to control mice where action potentials were always restricted to the plateau phase of the slow waves and the slow wave frequency remained constant at approximately 39 cpm. Our data provide further strong support for the identification of ICC-AP as small-intestinal pacemaker cells. In addition, they provide a basis for the understanding of intestinal motor function without pacemaker activity.

Exogenous Serotonin Regulates Proliferation of Interstitial Cells of Cajal in Mouse Jejunum Through 5-HT2B Receptors

“…We now know that there are several substances that help modulate ICC numbers in the gastrointestinal tract. The role of a functional c-Kit-stem cell factor pathway in the development 33,47,53,54 and maintenance of ICC 55 is well established. It recently became apparent that in a mouse gastroparesis model, a reduced insulin/insulin growth factor I (IGF-I) signaling pathway may lead to ICC depletion by causing smooth muscle atrophy and reduced SCF production.…”

IL-9 enhances growth of ICC, maintains network structure and strengthens rhythmicity of contraction in culture

“…In the WW v mouse which has a mutation in the c-kit gene, ICC-AP of the intestine develop through the embryonic period but do not develop further after birth [15]. ICC and mast cells are the only c-kit positive cells in the gut musculature and stem cell factor is critical for growth and differentiation of both cell types [21,23]. Extensive research from Ordog and co-workers has revealed that insulin or insulinlike growth factor type-1 (IGF-I) are likely essential growth factors for ICC [8,9,22].…”

Kit Signaling Is Required for Development of Coordinated Motility Patterns in Zebrafish Gastrointestinal Tract

“…Furthermore, mutant mouse models with loss of Kit signaling lack specific classes of ICC and do not have normal motility patterns. 2,[11][12][13] Two important examples are the compound heterozygote W/W v mutant, a Kit mutant with &90% loss of Kit signaling, and the compound heterozygote Sl/Sl d mutant that partially lacks a membrane-bound form of Kit ligand. 2,13 Both mutants are viable but have severely dilated intestine, incomplete ICC networks, and disrupted GI motility patterns.…”