Glial regulation of critical period plasticity

Animal behavior, from simple to complex, is dependent on the faithful wiring of neurons into functional neural circuits. Neural circuits undergo dramatic experience-dependent remodeling during brief developmental windows called critical periods. Environmental experience during critical periods of plasticity produces sustained changes to circuit function and behavior. Precocious critical period closure is linked to autism spectrum disorders, whereas extended synaptic remodeling is thought to underlie circuit dysfunction in schizophrenia. Thus, resolving the mechanisms that instruct critical period timing is important to our understanding of neurodevelopmental disorders. Control of critical period timing is modulated by neuron-intrinsic cues, yet recent data suggest that some determinants are derived from neighboring glial cells (astrocytes, microglia, and oligodendrocytes). As glia make up 50% of the human brain, understanding how these diverse cells communicate with neurons and with each other to sculpt neural plasticity, especially during specialized critical periods, is essential to our fundamental understanding of circuit development and maintenance

Stac3 is a component of the excitation–contraction coupling machinery and mutated in Native American myopathy

Excitation-contraction coupling, the process that regulates contractions by skeletal muscles, transduces changes in membrane voltage by activating release of Ca2+ from internal stores to initiate muscle contraction. Defects in EC coupling are associated with muscle diseases. Here we identify Stac3 as a novel component of the EC coupling machinery. Using a zebrafish genetic screen, we generate a locomotor mutation that is mapped to stac3. We provide electrophysiological, Ca2+ imaging, immunocytochemical and biochemical evidence that Stac3 participates in excitation-contraction coupling in muscles. Furthermore, we reveal that a mutation in human STAC3 as the genetic basis of the debilitating Native American myopathy (NAM). Analysis of NAM stac3 in zebrafish shows that the NAM mutation decreases excitation-contraction coupling. These findings enhance our understanding of both excitation-contraction coupling and the pathology of myopathies

Swimming into prominence: the zebrafish as a valuable tool for studying human myopathies and muscular dystrophies

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99682/1/febs12412.pd

Impaired embryonic motility in dusp27 mutants reveals a developmental defect in myofibril structure

An essential step in muscle fiber maturation is the assembly of highly ordered myofibrils that are required for contraction. Much remains unknown about the molecular mechanisms governing the formation of the contractile apparatus. We identified an early embryonic motility mutant in zebrafish caused by integration of a transgene into the pseudophosphatase dual specificity phosphatase 27 (dusp27) gene. dusp27 mutants exhibit near complete paralysis at embryonic and larval stages, producing extremely low levels of spontaneous coiling movements and a greatly diminished touch response. Loss of dusp27 does not prevent somitogenesis but results in severe disorganization of the contractile apparatus in muscle fibers. Sarcomeric structures in mutants are almost entirely absent and only rare triads are observed. These findings are the first to implicate a functional role of dusp27 as a gene required for myofiber maturation and provide an animal model for analyzing the mechanisms governing myofibril assembly

Zebrafish G protein γ2 is required for VEGF signaling during angiogenesis

Vascular endothelial growth factor (VEGF) is a major mediator of pathologic angiogenesis, a process necessary for the formation of new blood vessels to support tumor growth. Historically, VEGF has been thought to signal via receptor tyrosine kinases, which are not typically considered to be G protein dependent. Here, we show that targeted knockdown of the G protein gng2 gene (Gγ2) blocks the normal angiogenic process in developing zebrafish embryos. Moreover, loss of gng2 function inhibits the ability of VEGF to promote the angiogenic sprouting of blood vessels by attenuating VEGF induced phosphorylation of phospholipase C-gamma1 (PLCγ1) and serine/threonine kinase (AKT). Collectively, these results demonstrate a novel interaction between Gγ2- and VEGF-dependent pathways to regulate the angiogenic process in a whole-animal model. Blocking VEGF function using a humanized anti-VEGF antibody has emerged as a promising treatment for colorectal, non-small lung cell, and breast cancers. However, this treatment may cause considerable side effects. Our findings provide a new opportunity for cotargeting G protein- and VEGF-dependent pathways to synergistically block pathologic angiogenesis, which may lead to a safer and more efficacious therapeutic regimen to fight cancer. (Blood. 2006;108:160-166