Many cells can generate complementary traveling waves of actin filaments (F-actin) and cytoskeletal regulators. This phenomenon, termed cortical excitability, results from coupled positive and negative feedback loops of cytoskeletal regulators. The nature of these feedback loops, however, remains poorly understood. We assessed the role of the Rho GAP RGA-3/4 in the cortical excitability that accompanies cytokinesis in both frog and starfish. RGA-3/4 localizes to the cytokinetic apparatus, “chases” Rho waves in an F-actin–dependent manner, and when coexpressed with the Rho GEF Ect2, is sufficient to convert the normally quiescent, immature Xenopus oocyte cortex into a dramatically excited state. Experiments and modeling show that changing the ratio of RGA-3/4 to Ect2 produces cortical behaviors ranging from pulses to complex waves of Rho activity. We conclude that RGA-3/4, Ect2, Rho, and F-actin form the core of a versatile circuit that drives a diverse range of cortical behaviors, and we demonstrate that the immature oocyte is a powerful model for characterizing these dynamics.
To investigate the timing and intensity of winter spawning by coastal invertebrates, we enumerated embryos in plankton samples collected in daily time series from January to March of 2014 (79 d), 2015 (73 d), and 2016 (74 d). Samples were collected near the mouth of the Coos Bay estuary in Oregon. We enumerated several hundred different morphologically distinct types of embryos and larvae representing at least five phyla. Forty‐three embryo types were abundant enough (abundance > 500 over the time series) to enable statistical analysis. Twenty of these types were identified using genetic barcoding of which there were four nemerteans, four gastropods, four chitons, five polychaetes, and two echinoderms. In winter 2014, hydrographic conditions were similar to average historical values. Conditions in 2015 and 2016 were characterized by marine heat waves (MHWs). In 2015, the “warm blob”—anomalously warm water in the Northeastern Pacific—affected conditions and in 2016, there was a strong El Niño. In 2015 and 2016, winter spawning intensity was orders of magnitude lower than in 2014 and many taxa failed to spawn (11 and 24 in 2015 and 2016, respectively); spawning appears to have been adversely impacted by the MHWs. The MHW of 2015 has been attributed to anthropogenic global climate change while the 2016 El Niño may have been strengthened by climate change. The frequency, intensity, and duration of MHW are projected to increase dramatically with global warming, which may adversely affect reproduction and recruitment by numerous marine taxa.
Many cells can generate complementary traveling waves of actin filaments (F-actin) and cytoskeletal regulators. This phenomenon, termed cortical excitability, results from coupled positive and negative feedback loops of cytoskeletal regulators. The nature of these feedback loops, however, remains poorly understood. We assessed the role of the Rho GAP RGA-3/4 in the cortical excitability that accompanies cytokinesis in both frog and starfish. RGA-3/4 localizes to the cytokinetic apparatus, “chases” Rho waves in an F-actin-dependent manner and, when co-expressed with the Rho GEF Ect2, is sufficient to convert the normally quiescent, immature Xenopus oocyte cortex into a dramatically excited state. Experiments and modeling show that changing the ratio of RGA-3/4 to Ect2 produces a range of cortical behaviors from pulses to complex waves of Rho activity. We conclude that RGA-3/4, Ect2, Rho and F-actin form the core of a circuit that drives a diverse range of cortical behaviors, and demonstrate that the immature oocyte is a powerful model for characterizing these dynamics.SummaryMichaud et al. identify Ect2 and RGA-3/4 as core components of the cortical excitability circuit associated with cytokinesis. Additionally, they demonstrate that the immature Xenopus oocyte is a powerful model for characterizing excitable dynamics.
Cerebral cavernous malformations (CCMs) are vascular anomalies of the central nervous system that arise due to mutations in genes coding three unrelated proteins: CCM1 (KRIT1); CCM2 (Malcavernin/ OSM) and CCM3 (PDCD10). Both biochemical and mutant studies suggest that CCM1 and CCM2 act as part of a physical complex to regulate vascular morphogenesis and integrity. In contrast, mouse Ccm3 mutant and in vitro cell culture data suggests an independent role for Ccm3. We report that inhibition of zebrafish ccm3a/b causes heart and circulation defects distinct from those seen in ccm1 (santa) and ccm2 (valentine) mutants, and leads to a striking dilation and mispatterning of cranial vessels reminiscent of the human disease pathology. We further show that knockdown of ccm3 causes endothelial cells of the cranial vasculature to form hyperactive protrusions not seen in ccm1/2 mutants. ccm3, but not ccm2, defects can be rescued upon overexpression of stk25b, a GCKIII kinase previously shown to interact with CCM3. Morpholino knockdown of the GCKIII genes stk25b and mst4 results in heart and vasculature defects similar to those seen in ccm3 morphants. Finally, additional loss of ccm3 in ccm2 mutants leads to a synergistic increase in cranial vessel dilation. These results support a model in which CCM3 plays a role distinct from CCM1/2 in CCM pathogenesis, and acts via GCKIII activity to regulate cranial vasculature integrity and development. Our current work is focused on determining the specific cellular defects caused by disruption of Ccm3/Stk25 signaling and elucidating Ccm3 and Stk25b residues important for proper cranial vasculature development. Program/Abstract # 178The antagonistic functions of the activator and repressor forms of Gli proteins underlie the dorsoventral patterning of the wild type and mutant spinal cords Shh morphogen patterns the mouse spinal cord along its D/V axis through the dual-functional Gli transcription factors. How the activator and repressor forms of Gli proteins differentially contribute to spinal cord patterning remains controversial. We first addressed the roles of cilia in Gli1 activation in Gli21KI;Ift88 double mutant spinal cord. Gli1 can functionally replace Gli2 in supporting floor plate formation in Gli21KI, but not in Gli21KI;Ift88 double mutants, indicating that the full activation of Gli1 requires cilia. Surprisingly, V3 interneurons and motoneurons, which require moderate levels of Shh, are dorsally expanded only in double mutants, suggesting a cilia-independent basal activator activity of Gli1, as well as an important role for Gli repressors in spinal cord patterning. Consistent with the important roles of Gli repressors, V3 and motor neurons are dorsally expanded in Gli21KI;Gli3 double mutants. Sufu antagonizes Shh pathway and is critical for the spinal cord D/V patterning. It is under debate whether Sufu represses Shh signaling by directly repressing Gli activators or by stabilizing Gli2 and Gli3 repressors. Via a genetic approach, we show that the activator activities of Gli2...
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