The proto-oncogene c-kit encoding a transmembrane tyrosine kinase receptor maps to the mouse W locus

Abstract

Mice carrying mutations at the W locus located on chromosome 5 are characterized by severe macrocytic anaemia, lack of hair pigmentation and sterility. Mutations at this locus appear to affect the proliferation and/or migration of cells during early embryogenesis and result in an intrinsic defect in the haematopoietic stem cell hierarchy. An understanding of the molecular basis of the complex and pleiotropic phenotype in W mutant mice would thus provide insights into the important developmental processes of gametogenesis, melanogenesis and haematopoiesis. Here we show that the mouse mutant W has a deletion of the c-kit proto-oncogene. Interspecific backcross analysis demonstrates that the W locus is very tightly linked to c-kit and that the two loci cannot be segregated at this level of analysis. c-kit is the cellular homologue of the oncogene v-kit of the HZ4 feline sarcoma virus and encodes a transmembrane protein tyrosine kinase receptor that is structurally similar to the receptors for colony-stimulating factor-1 (CSF-1) and platelet derived growth factor. The co-localization of c-kit with W provides a molecular entry into this important region of the mouse genome. In addition, these observations provide the first example of a germ-line mutation in a mammalian proto-oncogene and implicate the c-kit gene as a candidate for the W locus.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…The involvement of cochlear melanocytes in generating the endocochlear potential was recognized later in a studies with “viable dominant spotting” mouse mutants, with a mutation in the W locus (Steel et al, 1987; Steel and Barkway, 1989). Shortly hereafter, Kit was found to be the gene product of the W locus (Chabot et al, 1988; Geissler et al, 1988), and it was shown to primarily affect the survival of migratory melanoblasts (Cable et al, 1995). In humans, KIT mutations can result in the neurocristopathy (a pathology affecting normal neural crest development) piebaldism [MIM 172800], a disorder characterized by areas of skin and hair devoid of melanocytes.…”

Efficient Enhancement of Lentiviral Transduction Efficiency in Murine Spermatogonial Stem Cells

“…We used W mutant mice as recipients for transplantation to examine whether transduced SSCs could restore the spermatogenesis of the recipient mouse that was congenitally infertile and lack endogenous spermatogenesis due to mutations in the c-Kit receptor tyrosine kinase gene. W mice were also chosen as it has been previously shown that efficient colonization by transplanted SSCs was enhanced in the W testis environment (Chabot et al, 1988;Geissler et al, 1988;Shinohara et al, 2001). Therefore, the presence of spermatogenesis inside the testes of W mice could only be derived from the transplanted donor SSCs.…”

Diffuse EGFR staining is associated with reduced overall survival in locally advanced oesophageal squamous cell cancer

“…CD117 (also known as c-kit) is a type-III tyrosine kinase receptor with five extracellular, immunoglobulin-like domains. This protein is strongly involved in myelopoiesis, melanogenesis and spermatogenesis (Yarden et al, 1987;Chabot et al, 1988). In some cancers such as gastro intestinal stromal tumours (GISTs), point mutations lead to abnormal expression and constitutive activity of the receptor.…”