Didier Hodzic, Ph.D.
Ophthalmology and Visual Sciences
Research Assistant Professor
Cell Biology and Physiology
Molecular Cell Biology Program
Developmental, Regenerative and Stem Cell Biology Program
620 McMillan Building
Sun proteins, Nesprins, Lamins, KASH domain, cell motility, interkinetic nuclear migration, eye development, transgenesis, Autosomal Recessive Cerebellar Ataxia TypeI (ARCA1)
Role of LINC complexes (Linkers of the Nucleoskeleton to the Cytoskeleton) in nucleokinesis and neuronal migration
“Linkers of the Nucleoskeleton to the Cytoskeleton” (LINC complexes) are macromolecular scaffolds that form through direct interactions between Sun proteins and Nesprins at the nuclear envelope. As a result, the cytoplasmic side of Nesprins provide anchoring sites for molecular motors and cytoskeletal networks to the nucleus. As such, LINC complexes mediate nuclear migration in different cellular settings. Nuclear movements within neuronal progenitors and post-mitotic neurons underlie fundamental aspects of CNS development. However, we still have a limited understanding of the physiological relevance of these nuclear movements during CNS development. Using a Cre/Lox-based transgenic strategy to interfere with the formation of LINC complexes within specific mouse cells and/or tissues, we study the role of LINC complexes in different nuclear movements during retinogenesis. The phenotypical consequences resulting from induced alterations of nuclear movements during retinogenesis are assessed using biochemical methods, immunofluorescence and time-lapse video microscopy as well as electrophysiology. Besides its canonical function at the nuclear envelope of many cell types, Nesprin1 is also expressed as a CNS-specific variant that does not associate with the nuclear envelope (see figure). Using novel mouse models, we currently evaluate the role of such variants in human diseases with a focus on the molecular etiology of Autosomal Recessive Ataxia TypeI, a pathology that has been linked to nonsense mutations of Nesprin1 and associated to a diverse spectrum of human pathologies.
Razafsky D, Ward C, Potter C, Zhu W, Xue Y, Kefalov VJ, Fong LG, Young SG, Hodzic D. Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development. Mol Biol Cell, 27(12):1928-37, 2016. PMCID: PMC4907726
Brightman DS, Razafsky D, Potter C, Hodzic D, Chen S.Nrl-Cre transgenic mouse mediates loxP recombination in developing rod photoreceptors. Genesis, 54(3):129-35, 2016. PMCID: PMC4803539
Razafsky D, Potter C, Hodzic D. Validation of a Mouse Model to Disrupt LINC Complexes in a Cell-specific Manner. J Vis Exp. 106:e53318, 2015. PMID: 26710083
Razafsky D, Hodzic D. Nuclear envelope: positioning nuclei and organizing synapses.
Curr Opin Cell Biol, 34:84-93, 2015. PMCID: PMC4522371
Razafsky, D. and Hodzic, D. A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of Autosomal Recessive Ataxia Type I. Neurobiology of Diseases, 78:57-67, 2015. PMCID: PMC4426048
Razafsky, D., Wirtz, D., Hodzic, D. Nuclear Envelope in Nuclear Positioning and Cell Migration. “Cancer Biology and the Nuclear Envelope”, Springer, New York (edited by Schirmer, E. and de la Hieras, J.) 773:471-90 (2014)
Razafsky, D. and Hodzic, D. Temporal and tissue-specific disruption of LINC complex disruption. Genesis, 52(4); 359-65 (2014)
Razafsky, D., Ward, C., Kolb, T., Hodzic, D. Developmental regulation of Linkers of the Nucleoskeleton to the Cytoskeleton during mouse postnatal retinogenesis. Nucleus, 4(5); 399-409 (2013)
Razafsky, D., Blecher, N., Markov, A., Stewart-Hutchinson, PJ., Hodzic, D. LINC complexes mediate the positioning of cone photoreceptor nuclei in mouse retina. Plos One, 7(10):e47180 (2012).
Khatau, S,B,, Bloom, R.J., Bajpai, S., Razafsky, D., Zang, S., Giri, A., Wu, P.H., Marchand, J., Celedon, A., Hale, C.M., Sun, S.X., Hodzic, D., Wirtz, D. The distinct roles of the nucleus and nucleus-cytoskeleton connections in three-dimensional cell migration. Sci Rep., 2:488. doi: 10.1038/srep00488 (2012).
Razafsky, D., Zang, S., Hodzic, D. UnLINcing the nuclear envelope: towards an understanding of the physiological significance of nuclear positioning. Biochem. Soc. Trans., 39:1790-1794 (2011).
Khatau, S.B., Hale C.M., Stewart-Hutchinson, P.J., Patel, M.S., Stewart, C.L., Searson, P.C., Hodzic, D., Wirtz, D. A perinuclear actin cap regulates nuclear shape. PNAS, 106:19017-22 (2009).
David Razafsky and Didier Hodzic. Bringing KASH under the SUN: The Many Faces of Nucleocytoskeletal connections, J. Cell Biol., 186: 461-72 (2009).
Stewart-Hutchinson, P.J, Hale, C.M., Wirtz D., Hodzic, D. Structural requirements for the assembly of LINC complexes and their function in cellular mechanical stiffness. Exp. Cell Res. 31:1892-1905 (2008).
Last Updated: 9/16/2016 9:21:11 AM
Immunofluorescence microscopy of lain B1 (red) and Nesprin1 (green) in the mouse cerebellum. Note the green "patches" of Nesprin1 signal surrounded by nuclei of cerebellar granule neurons (CGN, labeled with Lamin B1 in red). These patches correspond to large synapses between afferent mossy fibers and CGN dendrites.