The excretory cell is a simple model to study tubulogenesis. It forms an H-shaped unicellular tube composed of four long processes (canals) that encompass a single continuous intracellular lumen. We have shown that exc-6, which was identified in a pioneering screen for mutants with cystic excretory canals1, encodes an ortholog of the mammalian formin INF2, a kidney and neuropathy disease gene2. INF2, like other formins, is an actin-polymerizing factor, while it is unique in that it can also promote F-actin de-polymerization in vitro3. Moreover, INF2 has also been shown to regulate microtubules4, 5.
We demonstrated that exc-6 does not promote bulk F-actin polymerization in the excretory cell, and instead regulates F-actin accumulation at the leading edge of the canals and the dynamics of basolateral microtubules, contributing to coordination of basolateral outgrowth with apical lumen formation2. We also showed that exc-5, an activator of the Cdc42 family of Rho GTPases6, 7, regulates apical F-actin levels along the excretory cell lumen, and F-actin accumulation at the leading edge2. However, whether cdc-42 indeed acts downstream of exc-5, and what actin-polymerizing factor(s) function downstream of exc-5 remain open questions.
We have found that two other formins are expressed in the excretory cell, and are analyzing their contribution to excretory cell tubulogenesis. These formins are cyk-1, the sole member of the Diaphanous family of formins in C. elegans, and inft-2, another ortholog of INF2 (and thus a paralog of exc-6). Results from our genetic analysis are consistent with the hypothesis that cyk-1 and inft-2 function downstream of exc-5 in the excretory cell. We will report on our further studies of the interactions between these formins, and their potential regulation by exc-5 and cdc-42. Recent cell culture experiments suggest that mammalian INF2 negatively regulates the Diaphanous formin mDIA8, 9. Our work suggests that this regulatory relationship may be conserved and functionally relevant in vivo during tubulogenesis. Given that we found conservation of INF2 function between C. elegans and humans2, further characterizing the role and regulation of this network of formins has potential relevance for disease.
1) Buechner et al., 1999. 2) Shaye and Greenwald, 2015. 3) Chhabra and Higgs, 2006. 4) Gaillard et al., 2011. 5) Andrés-Delgado, et al., 2012. 6) Gao, et al., 2001. 7) Suzuki, et al., 2001. 8) Sun et al., 2011. 9) Sun et al., 2013.
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