Actin depolymerizing factors cofilin1 and destrin are required for ureteric bud branching morphogenesis.
The actin depolymerizing factors (ADFs) play important roles in several cellular processes that require cytoskeletal rearrangements, such as cell migration, but little is known about the in vivo functions of ADFs in developmental events like branching morphogenesis. While the molecular control of ureteric bud (UB) branching during kidney development has been extensively studied, the detailed cellular events underlying this process remain poorly understood. To gain insight into the role of actin cytoskeletal dynamics during renal branching morphogenesis, we studied the functional requirements for the closely related ADFs cofilin1 (Cfl1) and destrin (Dstn) during mouse development. Either deletion of Cfl1 in UB epithelium or an inactivating mutation in Dstn has no effect on renal morphogenesis, but simultaneous lack of both genes arrests branching morphogenesis at an early stage, revealing considerable functional overlap between cofilin1 and destrin. Lack of Cfl1 and Dstn in the UB causes accumulation of filamentous actin, disruption of normal epithelial organization, and defects in cell migration. Animals with less severe combinations of mutant Cfl1 and Dstn alleles, which retain one wild-type Cfl1 or Dstn allele, display abnormalities including ureter duplication, renal hypoplasia, and abnormal kidney shape. The results indicate that ADF activity, provided by either cofilin1 or destrin, is essential in UB epithelial cells for normal growth and branching.
Department of Genetics and Development, Columbia University Medical Center, New York, New York, United States of America.
Satu
S
Kuure
Cristina
C
Cebrian
Quentin
Q
Machingo
Benson C
BC
Lu
Xuan
X
Chi
Deborah
D
Hyink
Vivette
V
D'Agati
Christine
C
Gurniak
Walter
W
Witke
Frank
F
Costantini
D000199:Actins / Q000378:metabolism; D000818:Animals; D002465:Cell Movement; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D051345:Destrin / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D004848:Epithelium / Q000196:embryology / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology; D017403:In Situ Hybridization; D007668:Kidney / Q000187:drug effects / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis; D009924:Organ Culture Techniques; D014513:Ureter / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*
D000199:Actins; C495811:Cfl1 protein, mouse; D051338:Cofilin 1; D051345:Destrin; C495825:Dstn protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor