Sloan Kettering Institute New York

New York City, New York, United States

Sloan Kettering Institute New York

New York City, New York, United States
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PubMed | Sloan Kettering Institute New York and Chestnut Hill College
Type: | Journal: Frontiers in physiology | Year: 2013

Muscle disease as a group is characterized by muscle weakness, muscle loss, and impaired muscle function. Although the phenotype is the same, the underlying cellular pathologies, and the molecular causes of these pathologies, are diverse. One common feature of many muscle disorders is the mispositioning of myonuclei. In unaffected individuals, myonuclei are spaced throughout the periphery of the muscle fiber such that the distance between nuclei is maximized. However, in diseased muscles, the nuclei are often clustered within the center of the muscle cell. Although this phenotype has been acknowledged for several decades, it is often ignored as a contributor to muscle weakness. Rather, these nuclei are taken only as a sign of muscle repair. Here we review the evidence that mispositioned myonuclei are not merely a symptom of muscle disease but also a cause. Additionally, we review the working models for how myonuclei move from two different perspectives: from that of the nuclei and from that of the cytoskeleton. We further compare and contrast these mechanisms with the mechanisms of nuclear movement in other cell types both to draw general themes for nuclear movement and to identify muscle-specific considerations. Finally, we focus on factors that can be linked to muscle disease and find that genes that regulate myonuclear movement and positioning have been linked to muscular dystrophy. Although the cause-effect relationship is largely speculative, recent data indicate that the position of nuclei should no longer be considered only a means to diagnose muscle disease.


PubMed | Sloan Kettering Institute New York, University of Washington, Vanderbilt University and Seattle Childrens Research Institute
Type: | Journal: Frontiers in neural circuits | Year: 2015

Commissural neurons project across the midline at all levels of the central nervous system (CNS), providing bilateral communication critical for the coordination of motor activity and sensory perception. Midline crossing at the spinal ventral midline has been extensively studied and has revealed that multiple developmental lineages contribute to this commissural neuron population. Ventral midline crossing occurs in a manner dependent on Robo3 regulation of Robo/Slit signaling and the ventral commissure is absent in the spinal cord and hindbrain of Robo3 mutants. Midline crossing in the spinal cord is not limited to the ventral midline, however. While prior anatomical studies provide evidence that commissural axons also cross the midline dorsally, little is known of the genetic and molecular properties of dorsally-crossing neurons or of the mechanisms that regulate dorsal midline crossing. In this study, we describe a commissural neuron population that crosses the spinal dorsal midline during the last quarter of embryogenesis in discrete fiber bundles present throughout the rostrocaudal extent of the spinal cord. Using immunohistochemistry, neurotracing, and mouse genetics, we show that this commissural neuron population includes spinal inhibitory neurons and sensory nociceptors. While the floor plate and roof plate are dispensable for dorsal midline crossing, we show that this population depends on Robo/Slit signaling yet crosses the dorsal midline in a Robo3-independent manner. The dorsally-crossing commissural neuron population we describe suggests a substrate circuitry for pain processing in the dorsal spinal cord.


Dai Q.,Sloan Kettering Institute New York | Ren A.,Sloan Kettering Institute New York | Westholm J.O.,Sloan Kettering Institute New York | Westholm J.O.,University of Stockholm | And 3 more authors.
Genes and Development | Year: 2015

Recently, the BEN (BANP, E5R, and NAC1) domain was recognized as a new class of conserved DNA-binding domain. The fly genome encodes three proteins that bear only a single BEN domain (‘‘BEN-solo’’ factors); namely, Insensitive (Insv), Bsg25A (Elba1), and CG9883 (Elba2). Insv homodimers preferentially bind CCAATTGG palindromes throughout the genome to mediate transcriptional repression, whereas Bsg25A and Elba2 heterotrimerize with their obligate adaptor, Elba3 (i.e., the ELBA complex), to recognize a CCAATAAG motif in the Fab-7 insulator. While these data suggest distinct DNA-binding properties of BEN-solo proteins, we performed reporter assays that indicate that both Bsg25A and Elba2 can individually recognize Insv consensus sites efficiently. We confirmed this by solving the structure of Bsg25A complexed to the Insv site, which showed that key aspects of the BEN:DNA recognition strategy are similar between these proteins. We next show that both Insv and ELBA proteins are competent to mediate transcriptional repression via Insv consensus sequences but that the ELBA complex appears to be selective for the ELBA site. Reciprocally, genome-wide analysis reveals that Insv exhibits significant cobinding to class I insulator elements, indicating that it may also contribute to insulator function. Indeed, we observed abundant Insv binding within the Hox complexes with substantial overlaps with class I insulators, many of which bear Insv consensus sites. Moreover, Insv coimmunoprecipitates with the class I insulator factor CP190. Finally, we observed that Insv harbors exclusive activity among fly BEN-solo factors with respect to regulation of Notch-mediated cell fate choices in the peripheral nervous system. This in vivo activity is recapitulated by BEND6, a mammalian BEN-solo factor that conserves the Notch corepressor function of Insv but not its capacity to bind Insv consensus sites. Altogether, our data define an array of common and distinct biochemical and functional properties of this new family of transcription factors. © 2015 Dai et al.

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