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Research Highlights

**Please see the new website for updated research highlights.**

Our current work includes the development of new classes of molecular biosensors, which will allow us to monitor dozens of critical signaling pathways in real time. We are applying these new tools to investigate the fundamental cellular behaviors that underlie embryonic development, wound healing, cancer progression, and functions of the immune and nervous systems. Some recent publications are highlighted below.

David Yue Research

Soong TW, Yue DT. RNA editing of the IQ domain in Cav1.3 channels modulates their Ca2+-dependent inactivation. Neuron, Volume 3, page 304.

CaV1.3 Ca2+ channels figure critically in the rhythmicity of numerous oscillatory regions throughout the brain, including the circadian clock in suprachiasmatic nucleus. One of the ‘intelligent’ features of these channels is their Ca2+ negative feedback control system, enabling quantitative matching of channel Ca2+ influx to the needs of neuronal circuits. Ironically, this feature relies upon an ‘IQ’ domain (containing isoleucine and glutamine residues) situated on the carboxy tail of channels. Huang et al from the Soong and Yue laboratories now report that this IQ domain is RNA edited throughout the brain, yielding alternate versions of this critical motif, including the ‘MQ’ (methionine-glutamine) variant depicted in the cover. This editing allows exquisite molecular adjustment of Ca2+ negative feedback gain of CaV1.3 channels, which is shown to be important for rhythmicity in suprachiasmatic nucleus and likely numerous other brain regions.

Denise Montell Research

Kim, J. H., Cho, A., Yin, H., Schafer, D. A., Mouneimne, G., Simpson, K. J., Nguyen, K.V., Brugge, J. S. and Montell, D. J. Psidin, a Conserved Protein that Regulates Protrusion Dynamics and Cell Migration. Genes & Development, Volume 25, page 730.

Dynamic assembly and disassembly of actin filaments is a major driving force for cell movements. Border cells in the Drosophila ovary provide a simple and genetically tractable model to study the mechanisms regulating cell migration. To identify new genes that regulate cell movement in vivo, we screened lethal mutations on chromosome 3R for defects in border cell migration and identified two alleles of the gene psidin (psid). In vitro, purified Psid protein bound F-actin and inhibited the interaction of tropomyosin with F-actin. In vivo, psid mutations exhibited genetic interactions with the genes encoding tropomyosin and cofilin. Border cells over-expressing Psid together with GFP-actin exhibited altered protrusion/retraction dynamics. Psid knockdown in cultured S2 cells reduced, and Psid over-expression enhanced, lamellipodial dynamics.  Knockdown of the human homolog of Psid reduced the speed and directionality of migration in wounded MCF10A breast epithelial monolayers, whereas over-expression of the protein increased migration speed and altered protrusion dynamics in EGF stimulated cells. These results indicate that Psid is an actin regulatory protein, which plays a conserved role in protrusion dynamics and cell migration.

Li He Research

He, L., Wang, X., Tang, H. L. and Montell, D. J. Tissue elongation requires oscillating contractions of a basal actomyosin network. Nature Cell Biology, Volume 12, page 1133.

Understanding how molecular dynamics lead to cellular behaviors that ultimately sculpt organs and tissues is a major challenge not only in basic developmental biology but also in tissue engineering and regenerative medicine. We used live imaging to show that the basal surfaces of Drosophila follicle cells undergo a series of directional, oscillating contractions driven by periodic myosin accumulation on a polarized actin network.  Inhibition of the actomyosin contractions or their coupling to extracellular matrix (ECM) blocked elongation of the whole tissue, whereas enhancement of the contractions exaggerated it.  Myosin accumulated in a periodic manner prior to each contraction and was regulated by the small GTPase Rho, its downstream kinase ROCK and cytosolic calcium.  Disrupting the link between the actin cytoskeleton and the ECM decreased, while enhancing cell-ECM adhesion increased, the amplitude and period of the contractions.  In contrast, disrupting cell-cell adhesions resulted in loss of the actin network.  Our findings reveal a novel mechanism controlling organ shape and a new model for the study of the effects of oscillatory actomyosin activity within a coherent cell sheet.

Griffin Research

Griffin, E. E., Odde, D. J., Seydoux, G. Regulation of the MEX-5 Gradient by a Spatially Segregated Kinase/Posphatase Cycle. Cell, volume 146, page 955.

Protein concentration gradients encode spatial information across cells and tissues and often depend on spatially localized protein synthesis. Here, we report that a different mechanism underlies the MEX-5 gradient. MEX-5 is an RNA-binding protein that becomes distributed in a cytoplasmic gradient along the anterior-to-posterior axis of the one-cell C. elegans embryo. We demonstrate that the MEX-5 gradient is a direct consequence of an underlying gradient in MEX-5 diffusivity. The MEX-5 diffusion gradient arises when the PAR-1 kinase stimulates the release of MEX-5 from slow-diffusive, RNA-containing complexes in the posterior cytoplasm. PAR-1 directly phosphorylates MEX-5 and is antagonized by the spatially uniform phosphatase PP2A. Mathematical modeling and in vivo observations demonstrate that spatially segregated phosphorylation and dephosphorylation reactions are sufficient to generate stable protein concentration gradients in the cytoplasm. The principles demonstrated here apply to any spatially segregated modification cycle that affects protein diffusion and do not require protein synthesis or degradation.