CED-5/CED-12 (DOCK/ELMO) can promote and inhibit F-actin formation via distinct motifs that may target different GTPases.

Coordinated activation and inhibition of F-actin supports the movements of morphogenesis. Understanding the proteins that regulate F-actin is important, since these proteins are mis-regulated in diseases like cancer. Our studies of C.

CED-5/CED-12 (DOCK/ELMO) can promote and inhibit F-actin formation via distinct motifs that target different GTPases.

Coordinated activation and inhibition of F-actin supports the movements of morphogenesis. Understanding the proteins that regulate F-actin is important, since these proteins are mis-regulated in diseases like cancer. Our studies of embryonic epidermal morphogenesis identified the GTPase CED-10/Rac1 as an essential activator of F-actin.

WAVE facilitates polarized E-cadherin transport.

Cadherin dynamics drive morphogenesis, while defects in cadherin polarity contribute to diseases, including cancers. However, the forces polarizing cadherin membrane distribution are not well understood. We previously showed that WAVE-dependent branched actin polarizes cadherin distribution and suggested that one mechanism is protein transport.

E-Cadherin/HMR-1 Membrane Enrichment Is Polarized by WAVE-Dependent Branched Actin.

Polarized epithelial cells adhere to each other at apical junctions that connect to the apical F-actin belt. Regulated remodeling of apical junctions supports morphogenesis, while dysregulated remodeling promotes diseases such as cancer. We have documented that branched actin regulator, WAVE, and apical junction protein, Cadherin, assemble together in developing embryonic junctions.

Epithelial morphogenesis, tubulogenesis and forces in organogenesis.

As multi-cellular organisms evolved from small clusters of cells to complex metazoans, biological tubes became essential for life. Tubes are typically thought of as mainly playing a role in transport, with the hollow space (lumen) acting as a conduit to distribute nutrients and waste, or for gas exchange. However, biological tubes also provide a platform for physiological, mechanical, and structural functions.

RhoGAP RGA-8 supports morphogenesis in by polarizing epithelia.

CDC-42 regulation of non-muscle myosin/NMY-2 is required for polarity maintenance in the one-cell embryo of CDC-42 and NMY-2 regulate polarity throughout embryogenesis, but their contribution to later events of morphogenesis are less understood. We have shown that epidermal enclosure requires the GTPase CED-10/Rac1 and WAVE/Scar complex, its effector, to promote protrusions that drive enclosure through the branch actin regulator Arp2/3. Our analysis here of RGA-8, a homolog of SH3BP1/Rich1/ARHGAP17/Nadrin, with BAR and RhoGAP motifs, suggests it regulates CDC-42, so that actin and myosin/NMY-2 promote ventral enclosure during embryonic morphogenesis.

The RhoGAP HUM-7/Myo9 integrates signals to modulate RHO-1/RhoA during embryonic morphogenesis in .

During embryonic morphogenesis, cells and tissues undergo dramatic movements under the control of F-actin regulators. Our studies of epidermal cell migrations in developing embryos have identified multiple plasma membrane signals that regulate the Rac GTPase, thus regulating WAVE and Arp2/3 complexes, to promote branched F-actin formation and polarized enrichment. Here, we describe a pathway that acts in parallel to Rac to transduce membrane signals to control epidermal F-actin through the GTPase RHO-1/RhoA.

WAVE regulates Cadherin junction assembly and turnover during epithelial polarization.

Actin is an integral component of epithelial apical junctions, yet the interactions of branched actin regulators with apical junction components are still not clear. Biochemical data have shown that α-catenin inhibits Arp2/3-dependent branched actin. These results suggested that branched actin is only needed at earliest stages of apical junction development.

Sequential Rosettes Drive C. elegans Ventral Nerve Cord Assembly.

Planar cell polarity (PCP) signaling orients developmental events in vertebrates and invertebrates, including convergent extension (CE). In this issue of Development Cell, Shah and Tanner et al. (2017) report that ROBO/SAX-3 signaling acts in parallel with PCP signaling to drive the CE required for ventral nerve cord assembly in C.

WAVE/SCAR promotes endocytosis and early endosome morphology in polarized C. elegans epithelia.

Cells can use the force of actin polymerization to drive intracellular transport, but the role of actin in endocytosis is not clear. Studies in single-celled yeast demonstrate the essential role of the branched actin nucleator, Arp2/3, and its activating nucleation promoting factors (NPFs) in the process of invagination from the cell surface through endocytosis. However, some mammalian studies have disputed the need for F-actin and Arp2/3 in Clathrin-Mediated Endocytosis (CME) in multicellular organisms.

Wnt and CDK-1 regulate cortical release of WRM-1/β-catenin to control cell division orientation in early Caenorhabditis elegans embryos.

In early Caenorhabditis elegans embryos, the Wingless/int (Wnt)- and Src-signaling pathways function in parallel to induce both the division orientation of the endomesoderm (EMS) blastomere and the endoderm fate of the posterior EMS daughter cell, called E. Here, we show that, in addition to its role in endoderm specification, the β-catenin-related protein Worm armadillo 1 (WRM-1) also plays a role in controlling EMS division orientation. WRM-1 localizes to the cortex of cells in both embryos and larvae and is released from the cortex in a Wnt-responsive manner.

UNC-40/DCC, SAX-3/Robo, and VAB-1/Eph polarize F-actin during embryonic morphogenesis by regulating the WAVE/SCAR actin nucleation complex.

Many cells in a developing embryo, including neurons and their axons and growth cones, must integrate multiple guidance cues to undergo directed growth and migration. The UNC-6/netrin, SLT-1/slit, and VAB-2/Ephrin guidance cues, and their receptors, UNC-40/DCC, SAX-3/Robo, and VAB-1/Eph, are known to be major regulators of cellular growth and migration. One important area of research is identifying the molecules that interpret this guidance information downstream of the guidance receptors to reorganize the actin cytoskeleton.

The branched actin nucleator Arp2/3 promotes nuclear migrations and cell polarity in the C. elegans zygote.

Regulated movements of the nucleus are essential during zygote formation, cell migrations, and differentiation of neurons. The nucleus moves along microtubules (MTs) and is repositioned on F-actin at the cellular cortex. Two families of nuclear envelope proteins, SUN and KASH, link the nucleus to the actin and MT cytoskeletons during nuclear movements.

Arp2/3 promotes junction formation and maintenance in the Caenorhabditis elegans intestine by regulating membrane association of apical proteins.

It has been proposed that Arp2/3, which promotes nucleation of branched actin, is needed for epithelial junction initiation but is less important as junctions mature. We focus here on how Arp2/3 contributes to the Caenorhabditis elegans intestinal epithelium and find important roles for Arp2/3 in the maturation and maintenance of junctions in embryos and adults. Electron microscope studies show that embryos depleted of Arp2/3 form apical actin-rich microvilli and electron-dense apical junctions.

Requirements for F-BAR proteins TOCA-1 and TOCA-2 in actin dynamics and membrane trafficking during Caenorhabditis elegans oocyte growth and embryonic epidermal morphogenesis.

The TOCA family of F-BAR-containing proteins bind to and remodel lipid bilayers via their conserved F-BAR domains, and regulate actin dynamics via their N-Wasp binding SH3 domains. Thus, these proteins are predicted to play a pivotal role in coordinating membrane traffic with actin dynamics during cell migration and tissue morphogenesis. By combining genetic analysis in Caenorhabditis elegans with cellular biochemical experiments in mammalian cells, we showed that: i) loss of CeTOCA proteins reduced the efficiency of Clathrin-mediated endocytosis (CME) in oocytes.

The WAVE/SCAR complex promotes polarized cell movements and actin enrichment in epithelia during C. elegans embryogenesis.

The WAVE/SCAR complex promotes actin nucleation through the Arp2/3 complex, in response to Rac signaling. We show that loss of WVE-1/GEX-1, the only C. elegans WAVE/SCAR homolog, by genetic mutation or by RNAi, has the same phenotype as loss of GEX-2/Sra1/p140/PIR121, GEX-3/NAP1/HEM2/KETTE, or ABI-1/ABI, the three other components of the C.

The Arp2/3 activators WAVE and WASP have distinct genetic interactions with Rac GTPases in Caenorhabditis elegans axon guidance.

In the developing nervous system, axons are guided to their targets by the growth cone. Lamellipodial and filopodial protrusions from the growth cone underlie motility and guidance. Many molecules that control lamellipodia and filopodia formation, actin organization, and axon guidance have been identified, but it remains unclear how these molecules act together to control these events.

The WD40 and FYVE domain containing protein 2 defines a class of early endosomes necessary for endocytosis.

The FYVE domain binds with high specificity and avidity to phosphatidylinositol 3-phosphate. It is present in approximately 30 proteins in humans, some of which have been implicated in functions ranging from early endosome fusion to signal transduction through the TGF-beta receptor. To develop a further understanding of the biological roles of this protein family, we turned to the nematode Caenorhabditis elegans, which contains only 12 genes predicted to encode for phosphatidylinositol 3-phosphate binding, FYVE domain-containing proteins, all of which have homologs in the human genome.

UNC-6/netrin and SLT-1/slit guidance cues orient axon outgrowth mediated by MIG-10/RIAM/lamellipodin.

Background: Axon migrations are guided by extracellular cues that can act as repellants or attractants. However, the logic underlying the manner through which attractive and repulsive responses are determined is unclear. Many extracellular guidance cues, and the cellular components that mediate their signals, have been implicated in both types of responses.

The Conserved Kinases CDK-1, GSK-3, KIN-19, and MBK-2 Promote OMA-1 Destruction to Regulate the Oocyte-to-Embryo Transition in C. elegans.

Background: At the onset of embryogenesis, key developmental regulators called determinants are activated asymmetrically to specify the body axes and tissue layers. In C. elegans, this process is regulated in part by a conserved family of CCCH-type zinc finger proteins that specify the fates of early embryonic cells.

The Caenorhabditis elegans IMPAS gene, imp-2, is essential for development and is functionally distinct from related presenilins.

Presenilins (PSs) are required for Notch signaling in the development of vertebrates and invertebrates. Mutations in human PS1 and PS2 homologs are a cause of familial Alzheimer's disease (AD). The function of the recently identified ancient family of IMPAS proteins (IMP/SPP/PSH) homologous to PSs is not yet known.

SRC-1 and Wnt signaling act together to specify endoderm and to control cleavage orientation in early C. elegans embryos.

In early C. elegans embryos, signaling between a posterior blastomere, P2, and a ventral blastomere, EMS, specifies endoderm and orients the division axis of the EMS cell. Although Wnt signaling contributes to this polarizing interaction, no mutants identified to date abolish P2/EMS signaling.

The GEX-2 and GEX-3 proteins are required for tissue morphogenesis and cell migrations in C. elegans.

During body morphogenesis precisely coordinated cell movements and cell shape changes organize the newly differentiated cells of an embryo into functional tissues. Here we describe two genes, gex-2 and gex-3, whose activities are necessary for initial steps of body morphogenesis in Caenorhabditis elegans. In the absence of gex-2 and gex-3 activities, cells differentiate properly but fail to become organized.