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GF Erickson, L Fuqua, and S Shimasaki

Recent studies have demonstrated that bone morphogenetic proteins (BMPs) play fundamental roles in female fertility. This is particularly evident in terms of the ovary. One major question that is just beginning to be addressed is the role of BMPs in the non-pregnant uterus. To help fill this gap, we used in situ hybridization to investigate the expression of BMP family members in the rat uterus over the estrous cycle. We found that the endometrial/uterine cycle is accompanied by the expression of several components of the BMP pathway - including ligands, receptors and antagonists. The mRNAs encoding BMP receptors are expressed in the epithelial (BMP-RIA, -RIB and -RII), periluminal stroma (BMP-RIA and -RII) and smooth muscle cells (BMP-RIA and -RII). The expression of all three receptors showed clear cyclic variations. The mRNAs encoding BMP ligands were highly expressed in the periluminal stroma (BMP-2 and -7) and glandular epithelium (BMP-7). The expression of BMP-2, but not BMP-7, was cyclical. Notably, the periluminal stroma expressed noggin mRNA. In the blood vascular system, BMP-4, -6 and -RII mRNAs were expressed in myometrial endothelial cells. Interestingly, follistatin, noggin, and BMP-4, -6 and -7 mRNAs were expressed in eosinophilic leukocytes, suggesting unexpected roles for eosinophil-derived BMPs in uterine function. We conclude that BMP ligands, receptors and antagonists are expressed in spatially and temporally restricted patterns that are consistent with a physiological role for these regulatory molecules in promoting uterine cellular processes including cell proliferation, differentiation and apoptosis during the cycle.

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LD Wallen, W Myint, K Nygard, S Shimasaki, DR Clemmons, and VK Han

A role for IGF binding proteins (IGFBPs) in lung development is suggested by the identification of IGFBPs in lung tissue and production of IGFBPs by fetal lung cells in culture. To characterize the expression of IGFBPs during lung development in the rat in vivo (16 days gestation through adulthood), the expression of IGFBP mRNAs (IGFBP-1 to IGFBP-6) was examined by Northern analysis and in situ hybridization, and IGFBP peptides (IGFBP-2, IGFBP-3, and IGFBP-5) were localized by immunohistochemistry. IGFBP-1 mRNA was not detectable. IGFBP-2 mRNA (1.8 kb) was expressed in both fetal and postnatal life with peak expression during the fetal pseudoglandular stage. IGFBP-2 mRNA was localized mainly to airway epithelium. IGFBP-3 mRNA (2.4 kb) was maximally expressed postnatally in the saccular stage of lung development; it was identified in airway epithelium and interstitium in the fetal lung, but predominantly in airway epithelium after birth. IGFBP-4 (2.6 kb) and IGFBP-5 (6.0 kb) mRNA levels were maximal after birth, from 3 to 21 days postnatal (saccular and alveolar stage). IGFBP-4 mRNA was localized primarily to the interstitium and blood vessels early in development, but was abundant in airway epithelium in the adult. IGFBP-5 mRNA was most abundant in the airway epithelium. IGFBP-3, IGFBP-4, IGFBP-5, and to a lesser extent IGFBP-6 were localized to the large cartilaginous airways in the adult. IGFBP-2, IGFBP-3, and IGFBP-5 peptides were distributed more widely than their respective mRNAs, with a temporal pattern of immunoreactivity following that of their mRNAs. Maximal staining was noted in airway epithelium for IGFBP-2 in the newborn, for IGFBP-3 in the saccular stage (newborn to 3 days postnatal), and for IGFBP-5 in the alveolar stage (5 to 21 days postnatal). Our studies demonstrate that IGFBP-2, IGFBP-3, IGFBP-4, and IGFBP-5 are synthesized and distributed in spatially and temporally different patterns in the developing lung. The widespread distribution of IGFBP immunoreactivity compared with their respective mRNAs suggests that IGFBPs are important paracrine factors in the regulation of IGF action in the developing lung.

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S. G. Hillier, E. J. Wickings, P. T. K. Saunders, A. F. Dixson, S. Shimasaki, I. A. Swanston, L. E. Reichert Jr, and A. S. McNeilly


In-vitro data from experiments on rats implicate granulosa cells as primary sites of hormone-dependent ovarian inhibin biosynthesis, but no equivalent data exist for primates. We have used the common marmoset (Callithrix jacchus) to investigate inhibin biosynthesis in primate granulosa cells in vitro and to determine its relationship to preovulatory follicular development. To relate the production of immunoactive inhibin to follicular maturity, we studied primary granulosa cell cultures from follicles at progressive stages of preovulatory development. Granulosa cells from 'large' (≥2·0 mm diameter) follicles expressed high rates of inhibin production and steroidogenesis (progesterone), and were positively regulated by human (h)LH in vitro. Less mature granulosa cells from 'medium' (1·1–1·9 mm) and 'small' (≤ 1·0 mm) follicles expressed proportionately lower rates of inhibin production and steroidogenesis, but each parameter was stimulated in a dose- and time-dependent manner by hFSH in vitro. The stimulatory action of hFSH on immunoactive inhibin was augmented by the presence of testosterone or oestradiol; testosterone (but not oestradiol) also augmented the steroidogenic response to hFSH. Marmoset luteal tissue also produced inhibin in vitro and expressed an ∼1·5 kb inhibin α-subunit mRNA, confirming the corpus luteum as a source of ovarian inhibin in primates.

These results provide direct experimental evidence that primate granulosa cells produce inhibin. They suggest that production of inhibin by immature granulosa cells is initially induced by FSH and subject to modulation by follicular steroids. During advanced preovulatory development, granulosa cell inhibin production becomes directly responsive to LH, thereby indicating a role for LH in the control of peri- and postovulatory inhibin secretion by the primate ovary.

Journal of Endocrinology (1989) 123, 65–73