Broadening the educational pipeline: the global landscape of master of science programs in reproductive science and medicine.

Reproductive health underpins overall health, and thus, research in reproductive science and medicine is essential. This requires a pipeline of trained scientists and clinicians, which is challenging given the relatively small size of the field. Educational programs outside the traditional doctorate or medical degrees are needed to generate and maintain a well-trained reproductive science and medicine workforce. Master's programs have gained traction as a viable way for students to receive educational value relative to their career goals. Our hypothesis is master's degree programs in the fundamental, applied, and allied health reproductive fields broadens the workforce and increases impact. An internet web search identified 73 programs that conferred an MS degree in the areas of animal science, clinical/embryology, and reproductive health/biology. These programs are spread across the globe in Europe (47%), North America (23%), Asia (14%), South America (7%), Oceania (5%), and Africa (4%). To evaluate global exemplars, we profiled the mission and structure, curriculum, and program impact of two established master's degree programs: the Master of Science in Reproductive Science and Medicine at Northwestern University in the United States and the Biology and Technology of Reproduction in Mammals at the University of Murcia in Spain. Elements of infrastructure and support, program connectivity, and alumni networks were analyzed for their role in the success of the programs. These two programs have formally trained >375 individuals, demonstrating master's degree programs in reproductive science are an important educational mechanism. The educational best practices shared here serve as templates for expanding training programs worldwide.

The Notch effector gene Hes1 regulates migration of hypothalamic neurons, neuropeptide content and axon targeting to the pituitary.

Proper development of the hypothalamic-pituitary axis requires precise neuronal signaling to establish a network that regulates homeostasis. The developing hypothalamus and pituitary utilize similar signaling pathways for differentiation in embryonic development. The Notch signaling effector gene Hes1 is present in the developing hypothalamus and pituitary and is required for proper formation of the pituitary, which contains axons of arginine vasopressin (AVP) neurons from the hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON). We hypothesized that Hes1 is necessary for the generation, placement and projection of AVP neurons. We found that Hes1 null mice show no significant difference in cell proliferation or death in the developing diencephalon at embryonic day 10.5 (e10.5) or e11.5. By e16.5, AVP cell bodies are formed in the SON and PVN, but are abnormally placed, suggesting that Hes1 may be necessary for the migration of AVP neurons. GAD67 immunoreactivity is ectopically expressed in Hes1 null mice, which may contribute to cell body misplacement. Additionally, at e18.5 Hes1 null mice show continued misplacement of AVP cell bodies in the PVN and SON and additionally exhibit abnormal axonal projection. Using mass spectrometry to characterize peptide content, we found that Hes1 null pituitaries have aberrant somatostatin (SS) peptide, which correlates with abnormal SS cells in the pituitary and misplaced SS axon tracts at e18.5. Our results indicate that Notch signaling facilitates the migration and guidance of hypothalamic neurons, as well as neuropeptide content.

p21, an important mediator of quiescence during pituitary tumor formation, is dispensable for normal pituitary development during embryogenesis.

A delicate balance between proliferation and differentiation must be maintained in the developing pituitary to ensure the formation of the appropriate number of hormone producing cells. In the adult, proliferation is actively restrained to prevent tumor formation. The cyclin dependent kinase inhibitors (CDKIs) of the CIP/KIP family, p21, p27 and p57, mediate cell cycle inhibition. Although p21 is induced in the pituitary upon loss of Notch signaling or initiation of tumor formation to halt cell cycle progression, its role in normal pituitary organogenesis has not been explored. In wildtype pituitaries, expression of p21 is limited to a subset of cells embryonically as well as during the postnatal proliferative phase. Mice lacking p21 do not have altered cell proliferation during early embryogenesis, but do show a slight delay in separation of proliferating progenitors from the oral ectoderm. By embryonic day 16.5, p21 mutants have an alteration in the spatial distribution of proliferating pituitary progenitors, however there is no overall change in proliferation. At postnatal day 21, there appears to be no change in proliferation, as assessed by cells expressing Ki67 protein. However, p21 mutant pituitaries have significantly less mRNA of Myc and the cyclins Ccnb1, Ccnd1, Ccnd2 and Ccne1 than wildtype pituitaries. Interestingly, unlike the redundant role in cell cycle inhibition uncovered in p27/p57 double mutants, the pituitary of p21/p27 double mutants has a similar proliferation profile to p27 single mutants at the time points examined. Taken together, these studies demonstrate that unlike p27 or p57, p21 does not play a major role in control of progenitor proliferation in the developing pituitary. However, p21 may be required to maintain normal levels of cell cycle components.

The notch target gene HES1 regulates cell cycle inhibitor expression in the developing pituitary.

The pituitary is an endocrine gland responsible for the release of hormones, which regulate growth, metabolism, and reproduction. Diseases such as hypopituitarism or pituitary adenomas are able to disrupt pituitary function leading to suboptimal function of the entire endocrine system. Growth of the pituitary during development and adulthood is a tightly regulated process. Hairy and enhancer of split (HES1), a transcription factor whose expression is initiated by the Notch signaling pathway, is a repressor of cell cycle inhibitors. We hypothesize that with the loss of Hes1, pituitary progenitors are no longer maintained in a proliferative state, choosing instead to exit the cell cycle. To test this hypothesis, we examined the expression of cell cycle regulators in wild-type and Hes1-deficient pituitaries. Our studies indicate that in early pituitary development [embryonic day (e) 10.5], cells contained in the Rathke's pouch of Hes1 mutants have decreased proliferation, indicated by changes in phosphohistone H3 expression. Furthermore, pituitaries lacking Hes1 have increased cell cycle exit, shown by significant increases in the cyclin-dependent kinase inhibitors, p27 and p57, from e10.5 to e14.5. Additionally, Hes1 mutant pituitaries have ectopic expression of p21 in Rathke's pouch progenitors, an area coincident with increased cell death. These observations taken together indicate a role for HES1 in the control of cell cycle exit and in mediating the balance between proliferation and differentiation, allowing for the properly timed emergence of hormone secreting cell types.

Spatial regulation of Corazonin neuropeptide expression requires multiple cis-acting elements in Drosophila melanogaster.

Although most invertebrate neuropeptide-encoding genes display distinct expression patterns in the central nervous system (CNS), the molecular mechanisms underlying spatial regulation of the neuropeptide genes are largely unknown. Expression of the neuropeptide Corazonin (Crz) is limited to only 24 neurons in the larval CNS of Drosophila melanogaster, and these neurons have been categorized into three groups, namely, DL, DM, and vCrz. To identify cis-regulatory elements that control transcription of Crz in each neuronal group, reporter gene expression patterns driven by various 5' flanking sequences of Crz were analyzed to assess their promoter activities in the CNS. We show that the 504-bp 5' upstream sequence is the shortest promoter directing reporter activities in all Crz neurons. Further dissection of this sequence revealed two important regions responsible for group specificity: -504::-419 for DM expression and -380::-241 for DL and vCrz expression. The latter region is further subdivided into three sites (proximal, center, and distal), in which any combinations of the two are sufficient for DL expression, whereas both proximal and distal sites are required for vCrz expression. Interestingly, the TATA box does not play a role in Crz transcription in most neurons. We also show that a 434-bp 5' upstream sequence of the D. virilis Crz gene, when introduced into the D. melanogaster genome, drives reporter expression in the DL and vCrz neurons, suggesting that regulatory mechanisms for Crz expression in at least two such neuronal groups are conserved between the two species.