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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2010.05.007 Byline: Sarah Calve (a), Shannon J. Odelberg (b), Hans-Georg Simon (a) Keywords: Extracellular matrix; Time-lapse microscopy; 3D imaging; Skeletal muscle progenitor cells; Limb regeneration; Newt Abstract: Urodele amphibians regenerate appendages through the recruitment of progenitor cells into a blastema that rebuilds the lost tissue. Blastemal formation is accompanied by extensive remodeling of the extracellular matrix. Although this remodeling process is important for appendage regeneration, it is not known whether the remodeled matrix directly influences the generation and behavior of blastemal progenitor cells. By integrating in vivo 3-dimensional spatiotemporal matrix maps with in vitro functional time-lapse imaging, we show that key components of this dynamic matrix, hyaluronic acid, tenascin-C and fibronectin, differentially direct cellular behaviors including DNA synthesis, migration, myotube fragmentation and myoblast fusion. These data indicate that both satellite cells and fragmenting myofibers contribute to the regeneration blastema and that the local extracellular environment provides instructive cues for the regenerative process. The fact that amphibian and mammalian myoblasts exhibit similar responses to various matrices suggests that the ability to sense and respond to regenerative signals is evolutionarily conserved. Author Affiliation: (a) Department of Pediatrics, Northwestern University, The Feinberg School of Medicine, Children's Memorial Research Center, 2300 Children's Plaza, Chicago, IL 60614, USA (b) Department of Internal Medicine, Division of Cardiology, University of Utah, Salt Lake City, UT 84132, USA Article History: Received 15 March 2010; Revised 4 May 2010; Accepted 5 May 2010

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.ydbio.2006.07.027 Byline: Donald L. Atkinson (a), Tamara J. Stevenson (a), Eon Joo Park (b), Matthew D. Riedy (c), Brett Milash (d), Shannon J. Odelberg (a)(b)(c) Keywords: Dedifferentiation; Cellular plasticity; Regeneration; Electric field; Electroporation; Newt; Notophthalmus viridescens Abstract: Newts have the remarkable ability to regenerate lost appendages including their forelimbs, hindlimbs, and tails. Following amputation of an appendage, the wound is rapidly closed by the migration of epithelial cells from the proximal epidermis. Internal cells just proximal to the amputation plane begin to dedifferentiate to form a pool of proliferating progenitor cells known as the regeneration blastema. We show that dedifferentiation of internal appendage cells can be initiated in the absence of amputation by applying an electric field sufficient to induce cellular electroporation, but not necrosis or apoptosis. The time course for dedifferentiation following electroporation is similar to that observed following amputation with evidence of dedifferentiation beginning at about 5 days postelectroporation and continuing for 2 to 3 weeks. Microarray analyses, real-time RT-PCR, and in situ hybridization show that changes in early gene expression are similar following amputation or electroporation. We conclude that the application of an electric field sufficient to induce transient electroporation of cell membranes induces a dedifferentiation response that is virtually indistinguishable from the response that occurs following amputation of newt appendages. This discovery allows dedifferentiation to be studied in the absence of wound healing and may aid in identifying genes required for cellular plasticity. Author Affiliation: (a) Department of Internal Medicine, Division of Cardiology, University of Utah, Salt Lake City, UT 84132, USA (b) Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84132, USA (c) Interdepartmental Program in Neuroscience, University of Utah, Salt Lake City, UT 84132, USA (d) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84132, USA Article History: Received 15 March 2006; Revised 14 July 2006; Accepted 25 July 2006

Newts regenerate lost limbs through a complex process involving dedifferentiation, migration, proliferation, and redifferentiation of cells proximal to the amputation plane. To identify the genes controlling these cellular events, we performed a differential display analysis between regenerating and nonregenerating limbs from the newt Notophthalmus viridescens. This analysis, coupled with a direct cloning approach, identified a previously unknown Notophthalmus collagenase gene (nCol) and three known matrix metalloproteinase (MMP) genes, MMP3/ 10a, MMP3/10b, and MMP9, all of which are upregulated within hours of limb amputation. MMP3/10b exhibits the highest and most ubiquitous expression and appears to account for the majority of the proteolytic activity in the limb as measured by gel zymography. By testing purified recombinant MMP proteins against potential substrates, we show that nCol is a true collagenase, MMP9 is a gelatinase, MMP3/10a is a stromelysin, and MMP3/10b has an unusually broad substrate profile, acting both as a stromelysin and noncanonical collagenase. Exposure of regenerating limbs to the synthetic MMP inhibitor GM6001 produces either dwarfed, malformed limb regenerates or limb stumps with distal scars. These data suggest that MMPs are required for normal newt limb regeneration and that MMPs function, in part, to prevent scar formation during the regenerative process. Keywords: Limb regeneration; Matrix metalloproteinase; nCol; MMP3/10b; MMP3/10a; MMP9; Blastema; Notophthalmus viridescens; Newt

Results demonstrate that in the cell differentiation process, terminally differentiated mice myotubes can dedifferentiate through msx1 gene expression. Data indicate that clonal populations of the induced mononucleated cells redifferentiate into skeletal muscle cells upon receiving proper signals from the msx1 gene.

The developmental disorder Williams syndrome (WS) was studied to identify which genes are essential to human cognitive development. Two families with a partial WS phenotype were described, with affected family members having the specific WS cognitive profile but lacking other WS characteristics. Results show that the hemizygosity of the LIM-kinase1 protein kinase gene will likely result in impaired visuospatial constructive cognition in WS.

The chromosomal aberration associated with hereditary neuropathy with liability to pressure palsies (HNPP) was identified. Using DNA markers developed from Charcot-Marie-Tooth disease type 1 (CMT1), HNPP was attributed to a large deletion in 17p11.2 spanning 1.5 Mb and including all markers mapped to the duplicated region associated with CMT1A. It is proposed that HNPP and CMT1 are the products of unequal crossing over during meiosis, producing a deleted and duplicated region in chromosome 17, respectively.

Abstract: Cationic Rh(II) complexes are able to catalyze the regioselective hydroamination of propargyl ureas in a 6-endo fashion. This transformation permits access to interesting substitution patterns of dihydropyrimidines, which have found use as nucleotide exchange factor inhibitors. [Copyright &y& Elsevier]

Summary Activating mutations in Gαq proteins, which form the α subunit of certain heterotrimeric G proteins, drive uveal melanoma oncogenesis by triggering multiple downstream signaling pathways, including PLC/PKC, Rho/Rac, and YAP. Here we show that the small GTPase ARF6 acts as a proximal node of oncogenic Gαq signaling to induce all of these downstream pathways as well as β-catenin signaling. ARF6 activates these diverse pathways through a common mechanism: the trafficking of GNAQ and β-catenin from the plasma membrane to cytoplasmic vesicles and the nucleus, respectively. Blocking ARF6 with a small-molecule inhibitor reduces uveal melanoma cell proliferation and tumorigenesis in a mouse model, confirming the functional relevance of this pathway and suggesting a therapeutic strategy for Gα-mediated diseases. [ABSTRACT FROM AUTHOR]