Nuclear movements within neuronal progenitors and post-mitotic neurons underlie fundamental aspects of CNS development. Accordingly, failure of these nuclear movements are associated to severe neurodevelopmental defects such as abnormal cortical lamination, optic nerve hypoplasia and atrophy, retinal dysplasia, macular hypoplasia and microphthalmia. Our limited understanding of the physiological relevance of these nuclear movements stems, in part, from the current lack of appropriate animal models to interfere with nucleokinesis. We recently validated a novel transgenic strategy that interferes with nuclear movements within specific cells and/or tissues in vivo. This strategy is based on the inducible disruption of """"""""Linkers of the Nucleoskeleton to the Cytoskeleton"""""""" (LINC complexes), a family of macromolecular assemblies that span the nuclear envelope and provide anchor points for molecular motors and cytoskeletal networks to the nucleus. Using this transgenic strategy, we will examine the role of LINC complexes in interkinetic nuclear migration that consists of oscillations of retinal progenitor nuclei in phase with the cell cycle. Because nuclear translocation is strictly required for the migration of cortical post-mitotic neurons, we will examine whether LINC complex disruption affects the migration of newborn retinal neurons towards their final laminar position. The phenotypical consequences resulting from induced alterations of nuclear movements during retinogenesis will be fully examined in adult retinas, a set of results that may provide new models of congenital retinal disorders. We recently observed that cone nuclei positioning are severely altered upon LINC complex disruption, a phenotype that is strikingly similar to the progressive mispositioning of cone nuclei within the aging human retina. Here, the morphological and physiological consequences of cone nuclei mispositioning will be carefully analyzed in our mouse model. Cone nuclei mispositioning phenotype in adult retina originates from the inability of cone precursor nuclei to migrate apically during postnatal retinal development. Because B-type lamins directly interact with nucleoplasmic interfaces of LINC complexes, their involvement in cone nuclei positioning will be examined. Cytoplasmic interfaces of LINC complex are represented by Nesprins, a group of structurally- related proteins encoded by four distinct genes whose transcriptional regulation leads to the synthesis of multiple isoforms. Currently, the identity of Nesprin isoform(s) expressed in the CNS remains unknown, a knowledge gap that prevents the examination of the molecular nature of LINC complex interactions with molecular motors. Here, we will identify Nesprin isoforms expressed in retinal neurons and their progenitors. Because mutations of Nesprin genes are genetically linked to an increasing number of neurological disorders, our results may further emphasize CNS-specific isoforms of Nesprins whose mutations underlie human neurological disorders.

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We will examine the role of nuclear positioning during mammalian retinogenesis in vivo using a novel transgenic strategy that physically uncouples the nucleus from cytoskeletal networks and molecular motors. These results may identify new molecular mechanisms underlying fundamental aspects of retinal neurogenesis and lamination and provide novel molecular etiologies and mouse models related to congenital ocular disorders.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (BVS)
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Greenwell, Thomas
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Washington University
Schools of Medicine
Saint Louis
United States
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Potter, C; Razafsky, D; Wozniak, D et al. (2018) The KASH-containing isoform of Nesprin1 giant associates with ciliary rootlets of ependymal cells. Neurobiol Dis 115:82-91
Potter, Chloe; Zhu, Wanqiu; Razafsky, David et al. (2017) Multiple Isoforms of Nesprin1 Are Integral Components of Ciliary Rootlets. Curr Biol 27:2014-2022.e6
Brightman, Diana S; Razafsky, David; Potter, Chloe et al. (2016) Nrl-Cre transgenic mouse mediates loxP recombination in developing rod photoreceptors. Genesis 54:129-35
Razafsky, David; Ward, Candace; Potter, Chloe et al. (2016) Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development. Mol Biol Cell 27:1928-37
Razafsky, David; Potter, Chloe; Hodzic, Didier (2015) Validation of a Mouse Model to Disrupt LINC Complexes in a Cell-specific Manner. J Vis Exp :e53318
Razafsky, David; Hodzic, Didier (2015) A variant of Nesprin1 giant devoid of KASH domain underlies the molecular etiology of autosomal recessive cerebellar ataxia type I. Neurobiol Dis 78:57-67
Razafsky, David; Hodzic, Didier (2015) Nuclear envelope: positioning nuclei and organizing synapses. Curr Opin Cell Biol 34:84-93
Razafsky, David; Hodzic, Didier (2014) Temporal and tissue-specific disruption of LINC complexes in vivo. Genesis 52:359-65
Razafsky, David; Wirtz, Denis; Hodzic, Didier (2014) Nuclear envelope in nuclear positioning and cell migration. Adv Exp Med Biol 773:471-90
Razafsky, David S; Ward, Candace L; Kolb, Thorsten et al. (2013) Developmental regulation of linkers of the nucleoskeleton to the cytoskeleton during mouse postnatal retinogenesis. Nucleus 4:399-409

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