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Lamin B1 and Lamin B2 Are Long-Lived Proteins with Distinct Functions in Retinal Development

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Lamin B1 and Lamin B2 Are Long-Lived Proteins with Distinct Functions in Retinal Development M BoC | ARTICLE Lamin B1 and lamin B2 are long-lived proteins with distinct functions in retinal development David Razafskya, Candace Warda, Chloe Pottera, Wanqiu Zhua, Yunlu Xueb, Vladimir J. Kefalova, Loren G. Fongc, Stephen G. Youngc,d,e, and Didier Hodzica,* aDepartment of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110; bDepartment of Genetics, Harvard Medical School, Boston, MA 02115; cDepartment of Medicine, dDepartment of Human Genetics, and eMolecular Biology Institute, University of California, Los Angeles, Los Angeles, CA 90095 ABSTRACT Lamin B1 and lamin B2 are essential building blocks of the nuclear lamina, a fila- Monitoring Editor mentous meshwork lining the nucleoplasmic side of the inner nuclear membrane. Deficiencies Tom Misteli in lamin B1 and lamin B2 impair neurodevelopment, but distinct functions for the two pro- National Cancer Institute, NIH teins in the development and homeostasis of the CNS have been elusive. Here we show that Received: Mar 3, 2016 embryonic depletion of lamin B1 in retinal progenitors and postmitotic neurons affects nucle- Revised: Apr 6, 2016 ar integrity, leads to the collapse of the laminB2 meshwork, impairs neuronal survival, and Accepted: Apr 8, 2016 markedly reduces the cellularity of adult retinas. In stark contrast, a deficiency of lamin B2 in the embryonic retina has no obvious effect on lamin B1 localization or nuclear integrity in embryonic retinas, suggesting that lamin B1, but not lamin B2, is strictly required for nucleo- kinesis during embryonic neurogenesis. However, the absence of lamin B2 prevents proper lamination of adult retinal neurons, impairs synaptogenesis, and reduces cone photoreceptor survival. We also show that lamin B1 and lamin B2 are extremely long-lived proteins in rod and cone photoreceptors. OF interest, a complete absence of both proteins during postnatal life has little or no effect on the survival and function of cone photoreceptors. INTRODUCTION The nuclear lamina is a filamentous meshwork located adjacent to A-type lamins have attracted considerable interest, largely be- the inner nuclear membrane. It is composed of A-type lamins (lam- cause LMNA mutations have been implicated in a host of human ins A and C) and B-type lamins (lamins B1 and B2), all of which are genetic diseases, including muscular dystrophy, cardiomyopathy, type V intermediate filament proteins (Dechatet al., 2008; Worman partial lipodystrophy, and progeroid syndromes (Worman et al., et al., 2009). A-type lamins are alternatively spliced products of a 2009). Hundreds of mutations in LMNA have been documented, single gene, LMNA, whereas lamins B1 and B2 are encoded by and most cause dominantly inherited disease. When Lmna is inacti- separate genes, LMNB1 and LMNB2. LMNB1 and LMNB2 are ex- vated in mice, embryonic development is not affected, a finding pressed in all nucleated cells from the earliest stages of develop- consistent with the negligible levels of Lmna expression during de- ment, whereas LMNA is expressed at very low levels until late in velopment (Stewart and Burke, 1987; Rober et al., 1989; Coffinier embryonic development (Stewart and Burke, 1987; Rober et al., et al., 2011). However, Lmna-deficient mice succumb to muscular 1989; Coffinieret al., 2011). dystrophy and cardiomyopathy within weeks after birth. The synthe- sis of both lamin A and C is not required to prevent the emergence of disease phenotypes; lamin A–only mice and lamin C–only mice This article was published online ahead of print in MBoC in Press (http://www .molbiolcell.org/cgi/doi/10.1091/mbc.E16-03-0143). are healthy and entirely free of disease (Fong et al., 2006; Coffinier *Address correspondence to: Didier Hodzic ([email protected]). et al., 2010c; Davies et al., 2010). Abbreviations used: CAR, cone arrestin; INBL, inner neuroblast layer; INL, inner In comparison to A-type lamins, B-type lamins were neglected nuclear layer; ONBL, outer neuroblast layer; ONL, outer nuclear layer; OPL, outer for many years. One of the reasons for the reduced interest in plexiform layer; RGC, retinal ganglion cell; RPC, retinal progenitor cell. B-type lamins is a paucity of disease-causing mutations in LMNB1 © 2016 Razafsky et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is avail- and LMNB2. LMNB1 gene duplications have been shown to cause able to the public under an Attribution–Noncommercial–Share Alike 3.0 Unport- an adult-onset leukoencephalopathy (Padiath et al., 2006; Padiath ed Creative Commons License (http://creativecommons.org/licenses/by-nc -sa/3.0). and Fu, 2010), but, in contrast to the situation with LMNA, no mis- “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of sense or null mutations in LMNB1 have been linked to human dis- the Cell®” are registered trademarks of The American Society for Cell Biology. ease. In the case of LMNB2, a homozygous missense mutation was Volume 27 June 15, 2016 1 uncovered in two siblings with progressive myoclonus epilepsy Rx-Cre transgenic mice (Swindell et al., 2006). The Rx-Cre transgene (Damiano et al., 2015). A second reason for the relative neglect of is expressed in a variegated manner in the developing eye field, B-type lamins is that they were simply considered to be “house- beginning at embryonic day 9.5 (E9.5). As a result of the variegation keeping proteins” with unique and essential functions in the cell in Cre expression, the retinas of E14.5 Rx-CreLmnb1fl/fl mice (here nucleus, including DNA transcription and the assembly of the mi- called Rx-CreLmnb1Δ/Δ mice) had columns of RPCs expressing lamin totic spindle (Tsai et al., 2006; Dechat et al., 2008; Shimi et al., B1 adjacent to columns of RPCs devoid of lamin B1 expression 2008). However, similar to A-type lamins, B-type lamin depletion (Figure 1A). Immunostaining of the retina for Lap2β, an inner nuclear induces significant defects of nuclear structure both in vitro (Shimi membrane protein, revealed numerous nuclear blebs in lamin et al., 2008) and in vivo (Vergnes et al., 2004; Coffinieret al., 2010a, B1–deficient RPCs (Figure 1B). In the ONBL (distinguished by tightly 2011). packed cells and intense 4′,6-diamidino-2-phenylindole [DAPI] During the past few years, interest in B-type lamins has grown, staining), the nuclear blebs were found on either the apical or the primarily because of new insights from knockout models. Mice lack- basal side of RPC nuclei (Figure 1B, middle). In the INBL (located ing both B-type lamins in keratinocytes and hepatocytes have no beneath the ONBL), the nuclear blebs were found on the basal side obvious disease phenotypes (Yang et al., 2011a,b), casting consid- of adjacent nuclei (Figure 1B, bottom). In the INBL, micronuclei were erable doubt on the notion that B-type lamins play unique and es- often observed near a nucleus, likely representing nuclear blebs that sential roles in the cell nucleus. Of greater importance, Coffinier and had detached from the nucleus (Figure 1B, bottom, white arrow, coworkers created Lmnb1- and Lmnb2-knockout mice and discov- and Supplemental Figure S1A). These micronuclei contained chro- ered that deficiencies in either protein lead to neuronal layering ab- matin and were often topped with a Lap2β-positive thread (Supple- normalities in the cerebral cortex, a consequence of impaired mi- mental Figure S1, A and B). No micronuclei were detected in retinas gration of neurons from the ventricular zone to the cortical plate of Rx-CreLmnb1Δ/WT littermate control mice (Figure 1C). Thus lamin B1 during development (Coffinieret al., 2010a,b, 2011; Young et al., depletion in neurons in the ONBL and INBL results in striking mor- 2012). Those studies uncovered a role for B-type lamins in the brain, phological abnormalities in the cell nucleus. but key issues were left unresolved. One was an understanding of We next examined lamin B2 localization in E14.5 Rx-CreLmnb1Δ/Δ distinct effects of lamin B1 deficiency and lamin B2 deficiency in the retinas (Figure 2A). In cells lacking lamin B1, most of the lamin B2 development of the CNS. A second was whether B-type lamins are meshwork was located asymmetrically in one segment of the nu- important only during CNS development or remain equally crucial clear rim and often was found exclusively in a large nuclear bleb, in the CNS of adult mice after development is complete. suggesting that the lamin B2 meshwork had simply collapsed into To elucidate further the functions of B-type lamins in the devel- one segment of the nucleus. In contrast, Lap2β was symmetrically opment and homeostasis of the CNS, we created new knockout distributed along the entire circumference of the nucleus (Figure 2B). models that lacked lamin B1 and/or lamin B2 at different stages of In a few cells, small amounts of lamin B1 persisted and could be retinal development. We chose to examine the retina for several detected in nuclear blebs (Supplemental Figure S1A). reasons. First, like other regions of the CNS, retinal development is At E14.5, the ONBL is mostly populated by RPCs (Supplemental initiated from asymmetric divisions of retinal progenitor cells (RPCs) Figure S2A) and a population of newborn retinal ganglion cells on the apical side of the outer neuroblast layer (ONBL), generating (RGCs) that are migrating from the apical side of the ONBL toward postmitotic neurons that migrate toward the inner neuroblast layer the INBL. To determine whether RGCs are generated from RPCs in (INBL). Second, the retina is a nonessential region of the CNS; thus the absence of lamin B1, we stained E14.5 Rx-CreLmnb1Δ/Δ retinas one can avoid the early postnatal death of conventional Lmnb1- and with an antibody against Brn3 (a marker of RGCs) and an antibody Lmnb2-knockout mice (Vergnes et al., 2004; Coffinieret al., 2010a, against lamin B2.
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