An absence of lamin B1 in migrating neurons causes nuclear membrane ruptures and cell death.

Autor:	Chen NY; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Yang Y; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Weston TA; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Belling JN; California NanoSystems Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.; Department of Chemistry and Biochemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Heizer P; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Tu Y; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Kim P; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Edillo L; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095., Jonas SJ; Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.; Children's Discovery and Innovation Institute, University of California, Los Angeles, CA 90095.; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, CA 90095., Weiss PS; California NanoSystems Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.; Department of Chemistry and Biochemistry, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.; Department of Bioengineering, University of California, Los Angeles, CA 90095.; Department of Materials Science and Engineering, University of California, Los Angeles, CA 90095., Fong LG; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; lfong@mednet.ucla.edu sgyoung@mednet.ucla.edu., Young SG; Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095; lfong@mednet.ucla.edu sgyoung@mednet.ucla.edu.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.; Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Dec 17; Vol. 116 (51), pp. 25870-25879. Date of Electronic Publication: 2019 Dec 03.
DOI:	10.1073/pnas.1917225116
Abstrakt:	Deficiencies in either lamin B1 or lamin B2 cause both defective migration of cortical neurons in the developing brain and reduced neuronal survival. The neuronal migration abnormality is explained by a weakened nuclear lamina that interferes with nucleokinesis, a nuclear translocation process required for neuronal migration. In contrast, the explanation for impaired neuronal survival is poorly understood. We hypothesized that the forces imparted on the nucleus during neuronal migration result in nuclear membrane (NM) ruptures, causing interspersion of nuclear and cytoplasmic contents-and ultimately cell death. To test this hypothesis, we bred Lmnb1 -deficient mice that express a nuclear-localized fluorescent Cre reporter. Migrating neurons within the cortical plate of E18.5 Lmnb1 -deficient embryos exhibited NM ruptures, evident by the escape of the nuclear-localized reporter into the cytoplasm and NM discontinuities by electron microscopy. The NM ruptures were accompanied by DNA damage and cell death. The NM ruptures were not observed in nonmigrating cells within the ventricular zone. NM ruptures, DNA damage, and cell death were also observed in cultured Lmnb1 -/- and Lmnb2 -/- neurons as they migrated away from neurospheres. To test whether mechanical forces on the cell nucleus are relevant to NM ruptures in migrating neurons, we examined cultured Lmnb1 -/- neurons when exposed to external constrictive forces (migration into a field of tightly spaced silicon pillars). As the cells entered the field of pillars, there were frequent NM ruptures, accompanied by DNA damage and cell death. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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