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Interstitial Cells of Cajal in the Gastrointestinal Tract
AuthorFields, Mairead Joan
AdvisorWard, Sean M.
Biochemistry and Molecular Biology
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Interstitial cells of Cajal (ICC) are a specialized cell type of mesenchymal origin that exist within the tunica muscularis of the gastrointestinal (GI) tract. ICC (i) serve as pacemakers and possess unique ionic currents that allow them to generate spontaneous electrical slow waves in GI muscles; (ii) provide a pathway for the active propagation of slow waves around and along GI organs; (iii) regulate smooth muscle excitability by contributing to resting membrane potential and affecting syncytial conductance(s); (iv) express neural receptors, signaling mechanisms and ionic conductances allowing them to transduce post-junctional enteric motor nerve responses; (v) are capable of transducing stretch-dependent responses that regulate GI excitability and slow wave frequency; and (vi) have a trophic effect on vagal intramuscular array development and/or maintenance.Although the genetic fingerprint of ICCs is established prior to birth, significant changes in gene expression continue to occur after birth to configure the mature functional ICC networks and establish the SIP (smooth muscle/ interstitial cell/ PDGFR+ cell) syncytium. Kit expression is manifested in Kit+ precursor cells as early as E11 in the GI tract, though precursor cells only differentiate into functional ICC at a late embryonic stage. In the first 10 days after birth, electrical slow wave activity continues to be reinforced. Thus, functional gene expression develops in ICC in the mouse over approximately 20 days. In the present study, genes expressed in ICC from the emergence of Kit+ precursors to establishment of the mature phenotype were profiled.The Kit and Myh11 expression profiles support previous findings that ICC and smooth muscle cells emerge from a common precursor. In embryonic mice, levels of Kit expression throughout the GI tract were significantly lower than levels observed in adult tissues, consistent with postnatal reinforcement of Kit signaling. Ano1 expression was also significantly higher in ICC of mature animals compared to embryonic tissues, which correlates with postnatal development of more robust pacemaker activity. Elevated postnatal expression of additional transcripts important for pacemaker activity (Itpr1, Gja1) confirms this conclusion.ICC progenitors and emerging ICC also express important neurotrophic factors (ICC are targets for developing enteric or vagal nerve fibers). Transcripts for Glial cell-derived neurotrophic factor and brain-derived neurotrophic factor are expressed in ICC precursors in all regions of the GI tract. Expression of the Neurotrophin-3 transcript (Ntf3), which is essential for the survival and differentiation of neurons and their synapses, was relatively stable in ICC precursors and in emerging ICC populations. Expression of the Frizzled-3 transcript (Fzd3), which controls axon growth and the migration of neural crest cells, increased during embryonic development. Finally, ICC express transcripts for Dlg4 and Dlg2, which encode postsynaptic density protein 95 (PSD-95) and postsynaptic density protein 93 (PSD-93), respectively. PSD-95 and PSD-93 play an important role in synapse formation and stabilization. Dlg4 and Dlg2 expression increased during embryonic development, consistent with the development of neuroeffector junctions between enteric nerve terminals and ICC throughout the GI tract.Because reinforcement of Kit signaling occurs after birth, the GI tracts of newborn mice are more sensitive than adult tissues to the Kit neutralizing antibody ACK2. A mouse model of GI motility disorders was obtained through ACK2 disruption of the developing ICC networks. Here, ICC fate throughout the GI tract was assessed in neonatal animals from birth to P20 following disruption of Kit signaling with ACK2. The main objectives of this part of the study were: 1) To profile changes in postnatal expression of genes preferentially expressed in ICC after ACK2 treatment; and, 2) To determine whether loss of ICC is a consequence of decreased Kit receptor expression, dedifferentiation of ICC to an intermediate non-functional phenotype, or increased cell death.