Format

Send to

Choose Destination
Dev Cell. 2015 Mar 23;32(6):743-55. doi: 10.1016/j.devcel.2015.01.009. Epub 2015 Mar 12.

The disease-associated formin INF2/EXC-6 organizes lumen and cell outgrowth during tubulogenesis by regulating F-actin and microtubule cytoskeletons.

Author information

1
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: ds451@columbia.edu.
2
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA; Department of Genetics and Development, Columbia University, College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: isg4@columbia.edu.

Abstract

We investigate how outgrowth at the basolateral cell membrane is coordinated with apical lumen formation in the development of a biological tube by characterizing exc-6, a gene required for C. elegans excretory cell (EC) tubulogenesis. We show that EXC-6 is orthologous to the human formin INF2, which polymerizes filamentous actin (F-actin) and binds microtubules (MTs) in vitro. Dominant INF2 mutations cause focal segmental glomerulosclerosis (FSGS), a kidney disease, and FSGS+Charcot-Marie-Tooth neuropathy. We show that activated INF2 can substitute for EXC-6 in C. elegans and that disease-associated mutations cause constitutive activity. Using genetic analysis and live imaging, we show that exc-6 regulates MT and F-actin accumulation at EC tips and dynamics of basolateral-localized MTs, indicating that EXC-6 organizes F-actin and MT cytoskeletons during tubulogenesis. The pathology associated with INF2 mutations is believed to reflect misregulation of F-actin, but our results suggest alternative or additional mechanisms via effects on MT dynamics.

PMID:
25771894
DOI:
10.1016/j.devcel.2015.01.009
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center