Scf/c-kit Singnaling Acts As A New Etiologic Factor Of Depression By Regulating Adult Neurogenesis

Binding of Stem cell factor (SCF) to c‐Kit, a receptor tyrosine kinase, can transduct multiple signaling pathways. They mediate various biological processes, such as proliferation, survival, differentiation, migration, adhesion and chemotaxis. The vast archive of mutant animal models and related studies demonstrated that SCF/c‐Kit signaling is important for melanogenesis, hematopoiesis, gametogenesis, development of mast cells, interstitial cells of Cajal (ICCs). Although the first c‐kit mutant mouse strain was established one hundred years ago, knowledge of molecular and physiological functions of c‐Kit is still expanding rapidly.In this study, we identified and characterized a novel strain harboring point mutation in the c‐kit proto‐oncogene through ENU mutagenesis: c-KitV922G, with V922G substitution in the second kinase domain. Briefly, the heterozygous mice showed pigmentation defect, mast cell loss, big Caecum, and lymphocytes defect. Meanwhile, the homozygous mice are embryonic (perinatal) lethal. We also identified a novel mouse strain with belly white spot, Splotch3646. The point mutations were found both on exon6, a missense mutation of A894G, which caused the amino acid change of N272D on Homeodomain of Pax3, and on exon7, C1154T, a synonymous mutation. As it has been reported, the homozygotes are embryonic lethal which display limb abnormalties, exencephaly, heart defects and abnormal tail morphology.Moreover, we discovered that the heterozygous mice with V922G mutation in c-Kit display depression-like phenotype. In recent years, the dysfunction of adult hippocampal neurogenesis is proposed to be an essential mechanism explaining the etiology of depression.Yet few genetic mouse models can be obtained to assure that whether abnormal hippocampal neurogenesis is the cause or consequence of depression. Here we found that c-KitV922G/+ heterzygous mutants exhibited depression-like symptom around 2 month old, evaluated by behavior tests including forced swimming and tail suspension. The heterozygous mutant mice also showed delayed neuronal differentiation and increased proliferation in SGZ in adult hippocampal dentate gyrus. Furthermore, our case-control study in a cohort of 192 patients with major depression detected the correlation of a SNP (-1694G/T; rs6554199) in c-Kit promoter with major depression. Luciferase assay revealed that transcription activity of c-Kit promoter with the risk G allele, which had higher frequency in depression population, was significantly higher than the T allele SNP in HEK293T cell.Combination of evidences from mouse mutant analysis and genetic association study shed new light on the role of SCF/c-Kit signaling as an etiological factor for major depression by regulating hippocampal neurogenesis. This study deciphered the new function of c-Kit in neural system and provided the animal model for studying the depression etiology and multifunction of SCF/c-Kit signaling.