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    • KIT C KIT CD a

    2018-10-22

    KIT (C-KIT, CD117), a receptor tyrosine kinase (RTK), has been studied extensively in hematopoietic progenitors (Kent et al., 2008), but less is known about its function in epithelial progenitors. The ligand for KIT is stem cell factor (SCF), the gene product of Kitl. KIT signals via numerous pathways, including phosphatidylinositol 3-kinase (PI3K), phospholipase C γ (PLCγ), mitogen-activated protein kinase (MAPK), and Janus kinase/Signal Transducer and Activator of Transcription (JAK/STAT) (Lemmon and Schlessinger, 2010), and can transactivate other receptors (Jahn et al., 2007; Wu et al., 1995). Importantly, KIT-expressing (KIT+) progenitors form and regenerate various epithelial organs. Prostate tissue can be generated from a single KIT+ cell (Leong et al., 2008), epithelial-specific KIT+ progenitors functionally regenerate irradiated salivary glands (Lombaert et al., 2008; Nanduri et al., 2013), and KIT+ diindolylmethane repair lungs postthoracotomy (Kajstura et al., 2011). These findings suggest that epithelial KIT+ progenitors somehow lay the foundation for branching organ architecture. Importantly, the loss of KIT signaling due to a homozygous SNP (Chabot et al., 1988), Kit, is lethal by embryonic day 14 (E14) due to hematopoietic defects, but the effects of this mutation on epithelial progenitors and organogenesis are unclear. Severe defects in epithelial organogenesis occur in mice lacking Fgf10 or its receptor, Fgfr2b, and provide valuable insight into epithelial progenitor cell biology. Many organs, such as the salivary glands and lungs, do not form or are hypoplastic (De Moerlooze et al., 2000; Ohuchi et al., 2000). These phenotypes suggest defects in the survival, maintenance, and/or expansion of epithelial progenitors. In addition, mutations in fibroblast growth factor receptor 2 (FGFR2) and KIT occur in many epithelial tumors, and both receptors are being targeted with specific RTK inhibitors in breast, lung, liver, salivary gland, skin, renal, gastrointestinal, colorectal, ovarian, and uterine cancers (Casaletto and McClatchey, 2012; Hanahan and Weinberg, 2011; Lemmon and Schlessinger, 2010; Takeuchi and Ito, 2011). We thus hypothesized that an interaction between FGFR2b and KIT signaling could regulate epithelial progenitor expansion during organogenesis. To investigate this hypothesis, we studied mouse submandibular glands (SMGs), which develop by reiterative rounds of distal endbud and proximal duct formation, and require communication with the neuronal niche (Knox et al., 2010). We discovered that FGFR2b signaling upregulates the epithelial KIT pathway so that combined KIT/FGFR2b signaling, via separate AKT and MAPK pathways, amplifies FGFR2b-dependent transcription. The combined KIT and FGFR2b signaling increases the number of KIT+FGFR2b+ distal progenitors, but loss of KIT signaling depletes these progenitors. This KIT/FGFR2b-dependent mechanism is conserved during adult tissue homeostasis and in other branching organs.
    Results
    Discussion We propose that a similar conserved mechanism occurs in other organs, because FGFR2b signaling is required to initiate development of mammary, pituitary, and thyroid glands, as well as the kidney, pancreas, and prostate (Lin et al., 2007; Mailleux et al., 2002; Ohuchi et al., 2000). Similarly, KIT is expressed in these organs and is essential for kidney and prostate development (La Rosa et al., 2008; Leong et al., 2008; Li et al., 2007; Schmidt-Ott et al., 2006; Ulivi et al., 2004). Although previous studies have shown that FGFR2b signaling induces progenitor survival and proliferation (Bhushan et al., 2001; Ohuchi et al., 2000), we now demonstrate that it is a key upstream driver that induces distal KIT+ progenitor expansion. FGFR2b signaling achieves this by upregulating the KIT pathway to maintain KIT+-responsive progenitors. This is a critical event because combined KIT and FGFR2b signaling pathways converge at the transcriptional level to upregulate the expression of a conserved cassette of FGFR2b-dependent TFs in KIT+ progenitors. Distal progenitors of other organs, such as the pancreas (Kobberup et al., 2007) and limb (Zhang et al., 2009), express ETV4 and ETV5, which are part of this conserved TF cassette. Our experiments with L6 rat myoblasts also suggest that conserved TFs are upregulated when KIT and FGFR2b are overexpressed in cells where they are not normally present, and that for each cell type additional TFs may provide a cell-type-specific response.