Basement membranes are thin sheets of specialized extracellular matrix that surround all epithelia, endothelia, peripheral nerves, muscle cells, and fat cells. They are thought to play roles in filtration, in tissue integrity and compartmentalization, and in cell adhesion, proliferation, migration, and differentiation. Defects in basement membranes are responsible for a diverse array of human diseases, and the phenotypes of knockout mice show that basement membranes play critical roles during development and in mature tissues. The broad, long term goals of the research proposed here are to understand 1) the functions of basement membranes in mammalian development and physiology, and 2) how heterogeneity in basement membrane composition translates into functional specificity in vivo. We are particularly interested in one major component of all basement membranes, laminin. We previously showed that laminin alpha5 which is widely expressed, plays a crucial role in multiple developmental processes, including placentation and kidney development. In addition, replacement of alpha5 with a chimeric laminin in vivo demonstrated that the globular (G) domain of alpha5 is required for mesangial cell-mediated organization of the kidney glomerular capillaries. Here we will focus on the roles of the laminin alpha1 and alpha5 G domains in early embryogenesis and in formation of the placenta. We will also determine the cellular origin of the placental morphogenesis defect using Cre/lox technology. In addition, we will test the hypothesis that defects observed in the laminin alpha5 knockout stem in part from alterations in BMP signaling, which could result from abnormal interactions of BMPs or their antagonists with the extracellular matrix. The results of these studies will lead to new information regarding the assembly and function of laminins in the in vivo setting.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060432-08
Application #
7486255
Study Section
Special Emphasis Panel (ZRG1-ICI (01))
Program Officer
Flicker, Paula F
Project Start
2000-09-01
Project End
2011-08-31
Budget Start
2008-09-01
Budget End
2011-08-31
Support Year
8
Fiscal Year
2008
Total Cost
$254,601
Indirect Cost
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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Lin, Congxing; Werner, Ralf; Ma, Liang et al. (2016) Requirement for basement membrane laminin ?5 during urethral and external genital development. Mech Dev 141:62-9
Spenlé, Caroline; Simon-Assmann, Patricia; Orend, Gertraud et al. (2013) Laminin ?5 guides tissue patterning and organogenesis. Cell Adh Migr 7:90-100
Chen, Ying Maggie; Zhou, Yuefang; Go, Gloriosa et al. (2013) Laminin *2 gene missense mutation produces endoplasmic reticulum stress in podocytes. J Am Soc Nephrol 24:1223-33
Miner, Jeffrey H (2012) The glomerular basement membrane. Exp Cell Res 318:973-8
Chen, Ying Maggie; Miner, Jeffrey H (2012) Glomerular basement membrane and related glomerular disease. Transl Res 160:291-7
Kim, Sung Tae; Adair-Kirk, Tracy L; Senior, Robert M et al. (2012) Functional consequences of cell type-restricted expression of laminin *5 in mouse placental labyrinth and kidney glomerular capillaries. PLoS One 7:e41348
Miner, Jeffrey H (2011) Organogenesis of the kidney glomerulus: focus on the glomerular basement membrane. Organogenesis 7:75-82
Chen, Ying Maggie; Kikkawa, Yamato; Miner, Jeffrey H (2011) A missense LAMB2 mutation causes congenital nephrotic syndrome by impairing laminin secretion. J Am Soc Nephrol 22:849-58
Miner, Jeffrey H (2011) Glomerular basement membrane composition and the filtration barrier. Pediatr Nephrol 26:1413-7

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