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Iain
A. Drummond, PhD
Associate Professor of Medicine
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email:idrummon@receptor.mgh.harvard.edu Phone:
617-726-5647 (office) 617-724-9693 (lab)
website: http://danio.mgh.harvard.edu
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We are using
the zebrafish as a high-throughput system for gene discovery related
to podocyte function and as a model
of human podocyte disease for screening potentially therapeutic
small molecules.
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Personel
Yan Liu (Research Technologist)
Steve Mangos (Research Fellow)
Naren Pathak (Research Fellow)
Sudha Mudumana (Research Fellow)
Aleksandr Vasilyev (Research Fellow)
Asher Schacter (Visiting Professor)
References
Majumdar A. and Drummond I. A. Podocyte differentiation in
the absence of endothelial cells as revealed in the zebrafish
avascular mutant, cloche. Developmental Genetics 1999 24:220-229.
Majumdar, A., and I.A. Drummond. 2000. The zebrafish floating
head mutant demonstrates podocytes play an important role in
directing glomerular differentiation. Developmental Biology
222:147-157.
Majumdar, A., K. Lun, M. Brand, and I. A. Drummond. 2000. Zebrafish
no isthmus reveals a role for pax2.1 in tubule differentiation
and patterning events in the pronephric primordia. Development
127:2089-2098.
Serluca, F., I.A. Drummond, and M.C.Fishman. 2002 Endothelial
signaling in kidney morphogenesis. A role for hemodynamic forces.
Curr Biol. 12:492-7.
Drummond, I.A. and A. Majumdar 2002. The pronephric glomus
and vasculature. The Kidney. P. Vise, J.B.L. Bard. and A. Woolf
(eds). San Diego, Academic Press.
Kramer-Zucker, A.G., Wiessner, S., Jensen, A.M. and Drummond,
I. 2005. Organization of the pronephric filtration apparatus
in zebrafish requires Nephrin, Podocin and the FERM domain
protein Mosaic eyes. Developmental Biology, 285:316-29.
Hinkes, B. et al, 2006. Positional
cloning of PLCE1 mutations as the first cause of a nephrotic
syndrome variant which may be reversible. Nature Genetics,
12:1397-405.
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The barrier function
of podocytes depends upon the development of specialized cell-cell adhesion
complexes called slit-diaphragms that form between podocyte foot processes
surrounding glomerular blood vessels. Failure to form the slit-diaphragm
results in leakage of high molecular weight proteins into the blood filtrate
and urine, a condition called proteinuria.
We have shown that the zebrafish pronephros can be used as an assay system for
the development of glomerular function and to identify novel components of the
slit-diaphragm. We have characterized the function of the zebrafish homolog of
Nephrin, the disease gene associated with the congenital nephritic syndrome of
the Finnish type, and Podocin, the gene mutated in autosomal recessive steroid-resistant
nephrotic syndrome. Zebrafish nephrin and podocin are specifically expressed
in pronephric podocytes and are required for the development of pronephric podocyte
cell structure.
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Ultrastructurally, disruption
of nephrin or podocin expression results in a loss of slit-diaphragms at
72 and 96 hours post-fertilization and failure to form normal podocyte
foot processes.
We have also shown that
two novel genes, the band 4.1/FERM domain gene mosaic eyes, and phospholipase
C epsilon, are required in podocytes for proper formation of slit-diaphragm
cell-cell junctions. A functional assay of glomerular filtration barrier
revealed that absence normal nephrin, podocin, plce, or mosaic
eyes expression results in loss of glomerular filtration discrimination
and aberrant passage of high molecular weight substances into the glomerular
filtrate.
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