Formins are a family of regulators of actin and microtubule dynamics that are present in almost all eukaryotes. These proteins are involved in many cellular processes, including cytokinesis, stress fiber formation, and cell polarization. Here we review one sub-family of formins, the inverted formins. Inverted formins as a group break several formin stereotypes, having atypical biochemical properties and domain organization, and they have been linked to kidney disease and neuropathy in humans. In this review, we will explore recent research on members of the inverted formin sub-family in mammals, zebrafish, fruit flies, and worms.

Formins are regulators of actin filament dynamics. We demonstrate here that two formins, FHOD-1 and EXC-6, are important in the nematode Caenorhabditis elegans for ovulation, during which actomyosin contractions push a maturing oocyte from the gonad arm into a distensible bag-like organ, the spermatheca. EXC-6, a homolog of the disease-associated mammalian formin INF2, is highly expressed in the spermatheca, where it localizes to cell-cell junctions and to circumferential actin filament bundles. Loss of EXC-6 does not noticeably affect the organization the actin filament bundles, and causes only a very modest increase in the population of junction-associated actin filaments. Despite absence of a strong cytoskeletal phenotype, approximately half of ovulations in exc-6 mutants exhibit extreme defects, including failure of the oocyte to enter the spermatheca, or breakage of the oocyte as the distal spermatheca entrance constricts during ovulation. Loss of FHOD-1 alone has little effect, and we cannot detect FHOD-1 in the spermatheca. However, combined loss of these formins in double fhod-1;exc-6 mutants results in profound ovulation defects, with significant slowing of the entry of oocytes into the spermatheca, and failure of nearly 80% of ovulations. We suggest that EXC-6 plays a role directly in the spermatheca, perhaps by modulating the ability of the spermatheca wall to rapidly accommodate an incoming oocyte, while FHOD-1 may play an indirect role relating to its known importance in the growth and function of the egg-laying muscles.

Formins are regulators of actin filament dynamics. We demonstrate here that two formins, FHOD‐1 and EXC‐6, are important in the nematode Caenorhabditis elegans for ovulation, during which actomyosin contractions push a maturing oocyte from the gonad arm into a distensible bag‐like organ, the spermatheca. EXC‐6, a homolog of the disease‐associated mammalian formin INF2, is highly expressed in the spermatheca, where it localizes to cell‐cell junctions and to circumferential actin filament bundles. Loss of EXC‐6 does not noticeably affect the organization the actin filament bundles, and causes only a very modest increase in the population of junction‐associated actin filaments. Despite absence of a strong cytoskeletal phenotype, approximately half of ovulations in exc‐6 mutants exhibit extreme defects, including failure of the oocyte to enter the spermatheca, or breakage of the oocyte as the distal spermatheca entrance constricts during ovulation. Loss of FHOD‐1 alone has little effect, and we cannot detect FHOD‐1 in the spermatheca. However, combined loss of these formins in double fhod‐1;exc‐6 mutants results in profound ovulation defects, with significant slowing of the entry of oocytes into the spermatheca, and failure of nearly 80% of ovulations. We suggest that EXC‐6 plays a role directly in the spermatheca, perhaps by modulating the ability of the spermatheca wall to rapidly accommodate an incoming oocyte, while FHOD‐1 may play an indirect role relating to its known importance in the growth and function of the egg‐laying muscles. © 2016 The Authors. Cytoskeleton Published by Wiley Periodicals, Inc.

Epithelial cell–cell junctions have dual roles of accommodating morphological changes in an epithelium, while maintaining cohesion during those changes. An abundance of junction proteins has been identified, but many details on how intercellular junctions respond to morphological changes remain unclear. In Caenorhabditis elegans, the spermatheca is an epithelial sac that repeatedly dilates and constricts to allow ovulation. It is thought that the junctions between spermatheca epithelial cells undergo reversible partial unzipping to allow rapid dilation. Previously, we found that EXC‐6, a C. elegans protein homolog of the human disease‐associated formin INF2, is expressed in the spermatheca and promotes oocyte entry. We show here that EXC‐6 localizes toward the apical aspect of the spermatheca epithelial junctions, and that the EXC‐6‐labeled junction domains “unzip” and dramatically flatten with oocyte entry into the spermatheca. We demonstrate that the C‐terminal tail of EXC‐6 is necessary and sufficient for junction localization. Moreover, expression of the tail alone worsens ovulation defects, suggesting this region not only mediates EXC‐6 localization, but also interacts with other components important for junction remodeling.