CKD is a significant health concern with an underlying genetic component. Multiple genome-wide association studies (GWASs) strongly associated CKD with the shroom family member 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's 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 (Shroom3 Gt/+ ) 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.

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.

The original version of this Article contained a typographical error in the spelling of the author Daniela Fernandois, which was incorrectly given as Daniela Fernadois. This has now been corrected in the PDF and HTML versions of the Article.

Reduced nephron number is linked with chronic kidney disease and adult onset hypertension. Defects in the formation of nephrons are a major factor in determining nephron number. Multiple genome wide association studies have strongly linked SHROOM3 with altered kidney function and chronic kidney disease. Yet, the role of SHROOM3 in kidney function and nephron formation is not known. We utilized Shroom3‐/‐ and Shroom3+/‐ mutant mice containing a gene trap β‐galactosidase reporter to analyze Shroom3 expression. LacZ expression localized shroom3 to cap mesenchyme and podocytes throughout kidney development. LacZ expression was only observed in the collecting ducts after E15.5. LacZ expression was maintained in the podocyte and collecting ducts in mature kidneys. Immunohistochemistry using a Shroom3 antibody confirmed the dynamic spatial and temporal expression pattern. Histological analysis of kidneys from Shroom3‐/‐ mice demonstrated numerous condensed and cystic glomeruli at E13.5. Abnormal glomeruli demonstrated markedly reduced expression of the podocyte markers Wilms’ Tumor Suppressor‐1 (Wt‐1) and Nephrin in Shroom3‐/‐ mice at E13.5 and E14.5. Glomerular counting at E18.5 demonstrated a 1.6‐fold reduction in glomerular number in Shroom3‐/‐ mice when compared to wild type (n=3). Analysis of postnatal Shroom3 +/‐ mice revealed focal segmental glomerulosclerosis (FSGS), glomerular hypercellularity, and hydronephrosis. Postnatal expression of Wt‐1 was similar to wild‐type mice but nephrin expression was virtually absent. In summary Shroom3 exhibits a dynamic expression pattern and the absence of Shroom3 leads to early defects in nephrogenesis resulting in reduced glomerular number and postnatal glomerular diseases. We conclude that Shroom3 is required for nephron formation or maintenance.