In males, Mullerian inhibiting substance (MIS) mRNA was first detected on the medial aspect of the urogenital ridge early on the morning of day 13 of gestation before testicular differentiation was evident, and localized to the more obvious Sertoli cells later on embryonic day 13. MIS transcripts remained at maximal levels between 14.5 and 17.5 days gestation, while the Mullerian duct involutes, and remained high until birth. MIS gene expression decreased progressively after birth and, as germ cell meiosis increased, became barely detectable in the Sertoli cells of the seminiferous tubules. In female rats, MIS mRNA was first detected in the single layer of cuboidal granulosa cells surrounding larger primary follicles 3 days after birth, coincident with the initiation of follicular growth. As follicular growth progressed, MIS mRNA expression was high in preantral and small antral follicles, especially in those granulosa cells closest to the oocyte. MIS mRNA expression decreased gradually in larger antral follicles, remaining prominent only in the cumulus cells and the dividing population of granulosa cells closest to the lumen. MIS gene expression was absent in follicles with features of atresia and in the larger antral follicles. The expression of MIS mRNA in actively dividing Sertoli and granulosa cells correlates with the stages of germ cell division. These findings are suggestive of a role for MIS in the control of germ cell maturation.
Serinekhreonine kinase transmembrane proteins are a new family of growth factor signal transducers that includes several isoforms of the activin type I1 receptor and the type I1 receptor for transforming growth factor-p. In an effort to clone the receptor for Mullerian inhibiting substance, a member of the transforming growth factor-p superfamily, oligonucleotide primers designed from conserved regions of these receptors' kinase domains were used for PCR amplification of fetal rat urogenital ridge cDNA. We isolated four novel receptors in this manner (designated Rl-R4), each of which has structural features of the previously cloned kinases, including a small extracellular ligand-binding domain, a single hydrophobic transmembrane domain, and an intracellular serinekhreonine kinase domain. In addition, each has characteristic kinase subdomains and conserved serinekhreonine kinase sequences found in this family. Northern analysis revealed mRNA expression of R1-R4 in several tissues, including fetal urogenital ridge, testis, and ovary, as well as brain and lung. In situ hybridization further localized R1 to mesenchyme of the 14.5 to 15-day fetal rat Mullerian duct and to oocytes of preantral and antral follicles, sites that are consistent with the predicted localization of Mullerian inhibiting substance receptor. In addition, R2 localized specifically to seminiferous tubules of the postnatal testis. These newest members of the activin and transforming growth factor-p type I1 receptor family should help define the molecular mechanisms by which this ligand superfamily affects cell growth and differentiation via membrane phosphorylation.
Throughout the estrous cycle, Müllerian inhibiting substance (MIS) mRNA signals, as detected by in situ hybridization, were found to be intense in granulosa cells of growing preantral and small antral follicles, especially in the layer closest to the oocyte. Neither primordial follicles, typical atretic follicles, nor CL expressed detectable signals. MIS mRNA signals seen in the cumulus cells of preovulatory follicles at 1000 and 1600 h of proestrus sharply declined at 2400 h, just before ovulation. MIS mRNA signals were intense and uniform in all newly recruited growing antral and Graafian follicles (> 350 microns) at 1000 h of estrus but became heterogeneous in their expression of MIS on metestrus and diestrus and notably absent in atretic follicles; these findings suggest that MIS expression is correlated with recruited follicle selection and suppression with selection for atresia. The fact that all the MIS-positive growing follicles contain oocytes arrested in meiosis, coupled with previous experimental evidence that MIS inhibits germinal vesicle breakdown, suggests that MIS also might act as a regulator of oocyte maturation.
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