International Mammalian Genome Society

The 13th International Mouse Genome Conference
October 31-November 3, 1999

Table of Contents * Structure * Bioinformatics * Sequence * Mapping * New Tools * Gene Discovery * Developmental * Mutagenesis * Functional Genomics

G18 Sex-Specific Effects of ENU-Induced Steel Mutations on Germ Cell Development

A. Mahakali,1 L. B. Russell,2 N. G. Copeland,3 N. A. Jenkins,3 and M. A. Bedell1. 1Department of Genetics, University of Georgia, Athens, GA; 2Life Sciences Division, Oak Ridge National Laboratory, Oak Ridge, TN; 3ABL-Basic Research Program, NCI-FCRDC, Frederick, MD

The Steel (Sl) locus of mice encodes mast cell growth factor (Mgf) that is the ligand for the Kit receptor tyrosine kinase and is required for multiple stages of germ cell development. During migration of primordial germ cells (PGCs), Mgf acts as a survival factor by suppressing apoptosis. During postnatal germ cell development, Mgf promotes oocyte growth and folliculogenesis and is essential for spermatogonial proliferation. Previous studies have suggested that the membrane-bound isoform of Mgf is essential for all aspects of germ cell development. However, the cytoplasmic domain of membrane-bound Mgf may mediate sex-specific aspects of postnatal germ cell development (Brannan et al. Genes Dev. 6:1832, 1992). To gain more insight into Mgf functions, we have characterized the effects of two new ENU-induced Sl mutations on embryonic and postnatal germ cell development. Nucleotide sequencing has revealed that the Sl18ENURk allele contains a nonsense mutation in the extracellular domain of Mgf and is predicted to encode two soluble Mgf isoforms with C-terminal deletions. The Sl1ZENUe allele contains a missense mutation that affects an N-linked glycosylation site in the fourth alpha-helical domain of Mgf. Both Sl18ENURk and Sl1ZENUe exert sex-specific effects on fertility with males homozygous for either allele being sterile while females homozygous for either allele have limited fertility. To determine the basis for infertility we have examined embryonic and postnatal germ cell development in these mutants. Whole-mount staining for alkaline phosphatase activity at embryonic day 11.5 revealed that PGC numbers in Sl18ENURk/Sl18ENURk and Sl1ZENUe/Sl1ZENUe embryos were moderately reduced and only slightly reduced, respectively, compared to +/+ littermates. These observations represent the mildest effects of known Sl mutations on PGCs. In both Sl18ENURk/Sl18ENURk and Sl1ZENUe/Sl1ZENUe juvenile females oogenesis occurs essentially normally, however follicular structures are somewhat disorganized in the former. In comparison, spermatogenesis is severely defective in the Sl18ENURk/Sl18ENURk juvenile males and is characterized by early cessation of spermatogenesis. Interestingly, early stages of spermatogenesis in Sl1ZENUe/Sl1ZENUe males are relatively normal. Since Sl1ZENUe/Sl1ZENUe males are sterile, this suggests that the Sl1ZENUe mutation may affect a late stage of spermatogenesis. The effects of these mutations on germ cell development provide additional evidence that Mgf-mediated signaling during oogenesis is fundamentally different from that occurring during spermatogenesis. Furthermore, sex-specific functions of Mgf in germ cells do not appear to be mediated solely through the cytoplasmic domain.

Research sponsored by the National Cancer Institute, DHHS, under contract with ABL and the National Science Foundation, under grant number IBN-9728428.


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