Beyond the brain-Peripheral kisspeptin signaling is essential for promoting endometrial gland development and function

Uterine growth and endometrial gland formation (adenogenesis) and function, are essential for fertility and are controlled by estrogens and other regulators, whose nature and physiological relevance are yet to be elucidated. Kisspeptin, which signals via Kiss1r, is essential for fertility, primarily through its central control of the hypothalamic-pituitary-ovarian axis, but also likely through peripheral actions. Using genetically modified mice, we addressed the contributions of central and peripheral kisspeptin signaling in regulating uterine growth and adenogenesis. Global ablation of Kiss1 or Kiss1r dramatically suppressed uterine growth and almost fully prevented adenogenesis. However, while uterine growth was fully rescued by E2 treatment of Kiss1-/- mice and by genetic restoration of kisspeptin signaling in GnRH neurons in Kiss1r-/- mice, functional adenogenesis was only marginally restored. Thus, while uterine growth is largely dependent on ovarian E2-output via central kisspeptin signaling, peripheral kisspeptin signaling is indispensable for endometrial adenogenesis and function, essential aspects of reproductive competence

Developmental origins for kidney disease due to Shroom3 deficiency

CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroomfamilymember 3 (SHROOM3) gene, which encodes an actin-associated protein important in epithelial morphogenesis. However, the role of SHROOM3 in kidney development and function is virtually unknown. Studies in zebrafish and rat showed that alterations in Shroom3 can result in glomerular dysfunction. Furthermore, human SHROOM3 variants can induce impaired kidney function in animal models. Here, we examined the temporal and spatial expression of Shroom3 in the mammalian kidney. We detected Shroom3 expression in the condensing mesenchyme, Bowman\u27s capsule, and developing and mature podocytes in mice. Shroom3 null (Shroom3Gt/Gt) mice showed marked glomerular abnormalities, including cystic and collapsing/degenerating glomeruli, and marked disruptions in podocyte arrangement and morphology. These podocyte-specific abnormalities are associated with altered Rho-kinase/myosin II signaling and loss of apically distributed actin. Additionally, Shroom3 heterozygous (Shroom3Gt/+) mice showed developmental irregularities that manifested as adult-onset glomerulosclerosis and proteinuria. Taken together, our results establish the significance of Shroom3 in mammalian kidney development and progression of kidney disease. Specifically, Shroom3 maintains normal podocyte architecture in mice via modulation of the actomyosin network, which is essential for podocyte function. Furthermore, our findings strongly support the GWASs that suggest a role for SHROOM3 in human kidney disease

The Role of Shroom3 in Kidney Development

Chronic kidney disease (CKD) affects 10% of the population in industrialized nations. Recent genome wide association studies (GWAS) have correlated SHROOM3 with glomerular filtration rate and albuminuria. To elucidate Shroom3’s role in the kidney, I employed a gene trap mouse model (Shroom3Gt/Gt allele) that produces a non-functional Shroom3 protein. Shroom3 is expressed in the podocytes embryonically and in adulthood as well as other cell types. Shroom3 loss results in glomerular cysts and reduced glomerular number. Some Shroom3+/Gt and Shroom3Gt/Gt podocytes showed loss of apical ROCK1, pMLC and actin consistent with the role of Shroom3 in actin organization. Shroom3+/Gt also showed reduced glomerular number and cystic glomeruli and some adult Shroom3+/Gt have albuminuria, a sign of CKD. Therefore, Shroom3 is required for normal kidney development and reduced Shroom3 function can result in adult-onset kidney disease. This provides a mechanistic explanation for the GWAS studies in humans correlating SHROOM3 with CKD