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The kit-ligand (steel factor) and its receptor c-kit/W: pleiotropic roles in gametogenesis and melanogenesis
P Besmer1, K Manova, R Duttlinger
1Molecular Biology Program Sloan-Kettering Institute, New York, NY.
Abstract:
The c-kit receptor tyrosine kinase belongs to the PDGF/CSF-1/c-kit receptor subfamily. The kit-ligand, KL, also called steel factor, is synthesized from two alternatively spliced mRNAs as transmembrane proteins that can either be proteolytically cleaved to produce soluble forms of KL or can function as cell-associated molecules. The c-kit receptor kinase and KL are encoded at the white spotting (W) and steel (Sl) loci of the mouse, respectively. Mutations at both the W and the Sl locus cause deficiencies in gametogenesis, melanogenesis and hematopoiesis. The c-kit receptor is expressed in the cellular targets of W and Sl mutations, while KL is expressed in their microenvironment. In melanogenesis, c-kit is expressed in melanoblasts from the time they leave the neural crest and expression continues during embryonic development and in the melanocytes of postnatal animals. In gametogenesis c-kit is expressed in primordial germ cells, in spermatogonia, and in primordial and growing oocytes, implying a role at three distinct stages of gametogenesis. Many mutant alleles are known at W and Sl loci and their phenotypes vary in the degree of severity in the different cellular targets of the mutations. While many W and Sl alleles severely affect primordial germ cells (PGC), several mild Sl alleles have weak effects on PGCs and exhibit differential male or female sterility. Steel Panda (Sl(pan)) is a KL expression mutation in which KL RNA transcript levels are reduced in most tissues analyzed. In female Sl(pan)/Sl(pan) mice, ovarian follicle development is arrested at the one layered cuboidal stage as a result of reduced KL expression in follicle cells, indicating a role for c-kit in oocyte growth. Wsh is a c-kit expression mutation, which affects mast cells and melanogenesis. While the mast cell defect results from lack of c-kit expression, the pigmentation deficiency appears to stem from ectopic c-kit receptor expression in the somitic dermatome at the time of migration of melanoblasts from the neural crest to the periphery. It is proposed that the ectopic c-kit expression in Wsh mice affects early melanogenesis in a dominant fashion. The "sash" or white belt of Wsh/+ animals and some other mutant mice is explained by the varying density of melanoblasts along the body axis of wild-type embryos.
Insights
Mutations in the c-kit receptor and kit-ligand (KL) genes disrupt gametogenesis, melanogenesis, and hematopoiesis. These genes are crucial for cell development and function, with mutations leading to various developmental defects in mice.
Area of Science:
- Developmental Biology
- Genetics
- Cell Biology
Background:
- The c-kit receptor tyrosine kinase and its ligand, kit-ligand (KL), are key regulators of cellular development.
- Mutations in the genes encoding c-kit (white spotting, W) and KL (steel, Sl) in mice lead to deficiencies in gametogenesis, melanogenesis, and hematopoiesis.
- c-kit is expressed in target cells, while KL is found in their microenvironment, highlighting their interdependent roles.
Purpose of the Study:
- To investigate the roles of c-kit and KL in mouse development, focusing on their impact on gametogenesis and melanogenesis.
- To analyze the effects of specific mutations, such as Steel Panda (Sl(pan)) and Wsh, on c-kit and KL expression and downstream developmental processes.
- To elucidate the mechanisms by which c-kit and KL mutations cause distinct developmental phenotypes.
Main Methods:
- Analysis of mouse models with mutations at the W and Sl loci, including Sl(pan) and Wsh alleles.
- Examination of c-kit and KL expression patterns during embryonic and postnatal development.
- Phenotypic analysis of gametogenesis, melanogenesis, and hematopoiesis in mutant mice.
Main Results:
- Mutations at W and Sl loci cause severe defects in primordial germ cells (PGCs), with some mild Sl alleles showing differential sterility.
- Reduced KL expression in Sl(pan)/Sl(pan) mice leads to arrested ovarian follicle development, indicating c-kit's role in oocyte growth.
- The Wsh mutation, affecting c-kit expression, results in mast cell defects and pigmentation anomalies, potentially due to ectopic c-kit expression influencing melanoblast migration.
Conclusions:
- c-kit and KL signaling are essential for normal gametogenesis, melanogenesis, and hematopoiesis in mice.
- Differential expression patterns and specific mutations in c-kit and KL result in a range of developmental defects.
- Understanding these genetic interactions provides insights into the complex regulation of cell development and differentiation.