Role of Afadin Signaling in Nephron Tubulogenesis Project Summary/Abstract Formation of polarized epithelial tubules is central to the structure and function of the kidney. Despite its importance, there is a fundamental gap in understanding the earliest steps in tubulogenesis, namely how epithelia establish apical-basal polarity and generate a central lumen. Continued existence of this gap represents an important problem because, until it is filled, an understanding of developmental abnormalities of the kidney will remain largely incomprehensible. The objective of this application is to elucidate how apical- basal polarity is established and lumen formation initiated, focusing on the role of Afadin signaling in nephron formation. Afadin is an adaptor protein to the Nectin family of adhesion receptors. Our preliminary data identify Afadin as critical for establishing an apical surface and initiating lumen formation in developing mouse nephrons. To further elucidate the cellular and molecular mechanisms that initiate polarity and lumen formation, the proposed studies have three specific aims.
The first aim i s to characterize molecular steps of lumen formation in vivo and in great detail. These studies will generate a molecular timeline of lumen initiation through subcellular localization of polarity, trafficking, and junctional complexes, and through live imaging of lumen formation in mice. Once characterized, additional studies will begin to assign proteins to different stages in the pathway using mouse models.
The second aim i s to identify novel molecular mechanisms of apical polarity and lumen formation using an established 3D cell culture model. Specifically the proposed experiments will elucidate a detailed signaling pathway by which Nectins and Afadin initiate lumen formation.
The third aim will examine the role of Afadin in tubule regeneration after ischemic injury, emphasizing similarities to the developmental process. Together these studies will delineate fundamental steps in polarity and lumen initiation and provide an improved framework for understanding developmental and acquired disorders of renal tubules.
Formation of polarized epithelial tubules is essential to life. Completion of the proposed work is the first step toward understanding the stages and mechanisms by which apical-basal polarity and lumen formation occur in vivo in nephrons. Knowledge of the cellular and molecular mechanisms by which renal tubulogenesis occurs is critical for understanding the primary causes of congenital and acquired renal diseases of tubules.
|Zimmerman, Susan E; Hiremath, Chitkale; Tsunezumi, Jun et al. (2018) Nephronectin Regulates Mesangial Cell Adhesion and Behavior in Glomeruli. J Am Soc Nephrol 29:1128-1140|
|Nie, Mingzhu; Bal, Manjot S; Liu, Jie et al. (2018) Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6). J Biol Chem 293:16488-16502|
|Gao, Lei; Yang, Zhufeng; Hiremath, Chitkale et al. (2017) Afadin orients cell division to position the tubule lumen in developing renal tubules. Development 144:3511-3520|
|Azizoglu, D Berfin; Braitsch, Caitlin; Marciano, Denise K et al. (2017) Afadin and RhoA control pancreatic endocrine mass via lumen morphogenesis. Genes Dev 31:2376-2390|
|Marciano, Denise K (2017) A holey pursuit: lumen formation in the developing kidney. Pediatr Nephrol 32:7-20|
|Nie, Mingzhu; Bal, Manjot S; Yang, Zhufeng et al. (2016) Mucin-1 Increases Renal TRPV5 Activity In Vitro, and Urinary Level Associates with Calcium Nephrolithiasis in Patients. J Am Soc Nephrol 27:3447-3458|
|Nair, Vidhya R; Franco, Luis H; Zacharia, Vineetha M et al. (2016) Microfold Cells Actively Translocate Mycobacterium tuberculosis to Initiate Infection. Cell Rep 16:1253-1258|
|Zhu, Jili; Chaki, Moumita; Lu, Dongmei et al. (2016) Loss of diacylglycerol kinase epsilon in mice causes endothelial distress and impairs glomerular Cox-2 and PGE2 production. Am J Physiol Renal Physiol 310:F895-908|
|Scharn, Caitlyn R; Collins, Angela C; Nair, Vidhya R et al. (2016) Heme Oxygenase-1 Regulates Inflammation and Mycobacterial Survival in Human Macrophages during Mycobacterium tuberculosis Infection. J Immunol 196:4641-9|
|Yang, Zhufeng; Zimmerman, Susan E; Tsunezumi, Jun et al. (2016) Role of CD34 family members in lumen formation in the developing kidney. Dev Biol 418:66-74|
Showing the most recent 10 out of 12 publications