Juxtamembrane signaling via the membrane growth factor KitL is critical for Kit mediated functions. KitL has a conserved cytoplasmic domain and has been shown to possess a monomeric leucine-dependent basolateral targeting signal. To investigate the consequences in vivo of impaired basolateral KitL targeting in polarized epithelial cells, we have mutated this critical leucine to alanine using a knock-in strategy. KitL(L263A/L263A) mutant mice are pigmented normally and steady-state hematopoiesis is unaffected although peritoneal and skin mast cell numbers are significantly increased. KitL localization is affected in the Sertoli cells of the KitL(L263A/L263A) testis and testis size is reduced in these mice due to aberrant spermatogonial proliferation. Furthermore, the effect of the KitL L263A mutation on the testicular phenotype is dosage dependent. The tubules of hemizygous KitL(L263A/Sl) mice completely lack germ cells in contrast to the weaker testicular phenotype of KitL(L263A/L263A) mice. The onset of the testis phenotype coincides with the formation of tight junctions between Sertoli cells during postnatal development. Thus, the altered sorting of KitL is dispensable for hematopoietic and melanogenic lineages, yet is crucial in the testicular environment, where the basal membranes of adjacent polarized Sertoli cells form a niche for the proliferating spermatogonia.
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