I B Carlsson and M P E Laitinen contributed equally to this paper
AbstractThe receptor tyrosine c-Kit and its cognate ligand, c-Kit ligand (KL, stem cell factor, SCF), are involved in ovarian follicular development in several animal species. We studied the expression of KL and c-Kit using in situ hybridization and immunohistochemistry in donated human ovarian cortical tissue. The KL transcripts were expressed in granulosa cells of primary follicles, whereas the expression of c-Kit was confined to the oocyte and granulosa cells in primary and secondary follicles. We employed an ovarian organ culture using firstly serum-containing and then serum-free medium to study the effects of KL and an anti-c-Kit antibody, ACK2, on the development and survival of ovarian follicles in vitro. Culture of ovarian cortical slices for 7 days resulted in a 37% increase in the number of primary follicles and a 6% increase in secondary follicles. The proportion of viable follicles decreased in all cultures. The addition of KL (1, 10 and 100 ng/ml) into the culture media did not affect the developmental stages of the follicles or the proportion of atretic follicles. Inclusion of ACK2 (800 ng/ml) in the culture medium significantly increased the proportion of atretic follicles on days 7 (49 vs 28% in control cultures) and 14 (62 vs 38%) of culture. In conclusion, c-Kit and KL are expressed in human ovaries during follicular development. Blocking the c-Kit receptor induces follicular atresia. The KL/c-Kit signaling system is likely to control the survival of human ovarian follicles during early follicular development.
Reproduction (2006) 131 641-649Introduction During a woman's reproductive life less than 1% of the follicles present in the human ovary at birth reach the stage of ovulation, while the rest undergo atresia and are lost. Some of the follicles present at birth start to grow during infancy and childhood, but most of them remain in the resting stage until they either degenerate or enter the growth phase during adult life (Adashi 1991, Gougeon 1996. It is likely that the mechanism behind the loss of germ cells is apoptotic cell death (Tilly 1996). Follicle-stimulating hormone (FSH) has been considered to be a key survival factor for follicles from the antral follicular stage onwards (McGee et al. 1998). However, the regulators of early follicular survival are still poorly characterized.The c-Kit ligand (KL, also called stem cell factor, SCF), a ligand for the c-Kit proto-oncogene receptor tyrosine kinase, is a pluripotent growth factor involved in the differentiation and growth of certain stem cell lineages including hematopoietic stem cells, neuroblasts, melanoblasts and primordial germ cells (PGCs) (Galli et al. 1994). The expression of KL has been detected in granulosa cells in mouse ovaries, while c-Kit receptor is confined to the oocytes and theca interna cells (Manova et al. 1990, Horie et al. 1991, Keshet et al. 1991, Motro et al. 1991, Motro & Bernstein 1993. In contrast to mice, c-Kit protein and mRNA have been detected...