June 2012

New functions for nuclear lamins in the brain

 

Fig. 3 from Young et al minireview published in the May 11, 2012, issue of JBC showing immunostaining of cerebral cortex in Lmnb1 and Lmnb2 knock-out mice

A meshwork formed by four nuclear lamins (lamins A, C, B1 and B2) long has been recognized to provide structural support for the cell nucleus. In a recent Journal of Biological Chemistry minireview, “Nuclear lamins and brain development,” the laboratory of Stephen G. Young and Loren G. Fong reviewed recent publications indicating that the lamins are important in the brain.

Earlier studies had proposed that the B-type lamins (lamins B1 and B2) play unique and important roles in DNA replication and cell division, but the studies by Young and Fong showed that a complete absence of both lamin B1 and lamin B2 in skin cells or liver cells has no adverse consequences. Interestingly, however, the absence of either lamin B1 or lamin B2 causes severe defects in brain development. Mice lacking either protein die shortly after birth and have markedly abnormal brain structure, a consequence of defective migration of neurons. The migration of neurons during brain development is known to depend on the cell’s ability to move the cell nucleus forward within the cell. Young and co-workers proposed that the ability to move the cell nucleus is impaired by the loss of either lamin B1 or lamin B2, resulting in defective migration of neurons. Consistent with that explanation, they showed that the shape of neuronal cell nuclei is quite abnormal in the absence of lamin B1 or lamin B2. They speculated that certain neurodevelopmental abnormalities in humans ultimately will be linked to genetic defects in lamin B1 or lamin B2.

The A-type lamins, lamins A and C, have attracted considerable attention, because defects in those proteins have been linked to several devastating diseases including cardiomyopathy and muscular dystrophy. Also, a rare precocious aging syndrome, Hutchinson-Gilford progeria syndrome, is caused by a genetic defect that prevents the production of lamin A from a precursor protein, prelamin A. The abnormal prelamin A in HGPS causes aging-like disease in multiple tissues, but the central nervous system is spared. Recent studies by Young and Fong provide a plausible explanation for the absence of central nervous system disease: they showed that a microRNA in the brain, miR-9, markedly reduces prelamin A production by neurons and glial cells. This discovery expands our understanding of the regulation of lamin A synthesis and also points to new strategies for the treatment of lamin A diseases.


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