TY - JOUR
T1 - Zebrafish mutations affecting cilia motility share similar cystic phenotypes and suggest a mechanism of cyst formation that differs from pkd2 morphants
AU - Sullivan-Brown, Jessica
AU - Schottenfeld, Jodi
AU - Okabe, Noriko
AU - Hostetter, Christine L.
AU - Serluca, Fabrizio C.
AU - Thiberge, Stephan Y.
AU - Burdine, Rebecca D.
PY - 2008/2/15
Y1 - 2008/2/15
N2 - Zebrafish are an attractive model for studying the earliest cellular defects occurring during renal cyst formation because its kidney (the pronephros) is simple and genes that cause cystic kidney diseases (CKD) in humans, cause pronephric dilations in zebrafish. By comparing phenotypes in three different mutants, locke, swt and kurly, we find that dilations occur prior to 48 hpf in the medial tubules, a location similar to where cysts form in some mammalian diseases. We demonstrate that the first observable phenotypes associated with dilation include cilia motility and luminal remodeling defects. Importantly, we show that some phenotypes common to human CKD, such as an increased number of cells, are secondary consequences of dilation. Despite having differences in cilia motility, locke, swt and kurly share similar cystic phenotypes, suggesting that they function in a common pathway. To begin to understand the molecular mechanisms involved in cyst formation, we have cloned the swt mutation and find that it encodes a novel leucine rich repeat containing protein (LRRC50), which is thought to function in correct dynein assembly in cilia. Finally, we show that knock-down of polycystic kidney disease 2 (pkd2) specifically causes glomerular cysts and does not affect cilia motility, suggesting multiple mechanisms exist for cyst formation.
AB - Zebrafish are an attractive model for studying the earliest cellular defects occurring during renal cyst formation because its kidney (the pronephros) is simple and genes that cause cystic kidney diseases (CKD) in humans, cause pronephric dilations in zebrafish. By comparing phenotypes in three different mutants, locke, swt and kurly, we find that dilations occur prior to 48 hpf in the medial tubules, a location similar to where cysts form in some mammalian diseases. We demonstrate that the first observable phenotypes associated with dilation include cilia motility and luminal remodeling defects. Importantly, we show that some phenotypes common to human CKD, such as an increased number of cells, are secondary consequences of dilation. Despite having differences in cilia motility, locke, swt and kurly share similar cystic phenotypes, suggesting that they function in a common pathway. To begin to understand the molecular mechanisms involved in cyst formation, we have cloned the swt mutation and find that it encodes a novel leucine rich repeat containing protein (LRRC50), which is thought to function in correct dynein assembly in cilia. Finally, we show that knock-down of polycystic kidney disease 2 (pkd2) specifically causes glomerular cysts and does not affect cilia motility, suggesting multiple mechanisms exist for cyst formation.
KW - Cilia
KW - Cyst
KW - Kidney
KW - Nephron
KW - Pronephros
KW - Zebrafish
KW - kurly
KW - locke
KW - lrrc50
KW - oda7
KW - pkd2
KW - switch hitter
UR - http://www.scopus.com/inward/record.url?scp=39149144464&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=39149144464&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2007.11.025
DO - 10.1016/j.ydbio.2007.11.025
M3 - Article
C2 - 18178183
AN - SCOPUS:39149144464
SN - 0012-1606
VL - 314
SP - 261
EP - 275
JO - Developmental biology
JF - Developmental biology
IS - 2
ER -