Lamin B1 is essential for neuronal migration and progenitor proliferation during the development of the cerebral cortex. The observation of distinct phenotypes of Lmnb1- and Lmnb2-knockout mice and the differences in the nuclear morphology of cortical neurons in vivo suggest that lamin B1 and lamin B2 play distinct functions in the developing brain.

Nuclear lamins are components of the nuclear lamina, a structural scaffolding for the cell nucleus. Defects in lamins A and C cause an array of human diseases, including muscular dystrophy, lipodystrophy, and progeria, but no diseases have been linked to the loss of lamins B1 or B2. To explore the functional relevance of lamin B2, we generated lamin B2-deficient mice and found that they have severe brain abnormalities resembling lissencephaly, with abnormal layering of neurons in the cerebral cortex and cerebellum. This neuronal layering abnormality is due to defective neuronal migration, a process that is dependent on the organized movement of the nucleus within the cell. These studies establish an essential function for lamin B2 in neuronal migration and brain development.brain | lissencephaly | neuronal migration | nuclear envelope | nuclear lamina T he nuclear lamina is an intermediate filament meshwork lying beneath the inner nuclear membrane that provides a structural scaffolding for the nucleus (1). The lamina is also important for other processes, including gene transcription, chromatin organization, nuclear pore distribution, nuclear envelope assembly, and tethering of the nucleus to the cytoskeleton (1, 2). The main components of the nuclear lamina are nuclear lamins, a class of intermediate filament proteins that is generally divided into two groups, A-type (lamins A and C) and B-type (lamins B1 and B2) (3, 4). Lamins A and C are produced from LMNA by alternative splicing, whereas lamins B1 and B2 are encoded by distinct genes, LMNB1 and LMNB2, respectively. Lamins B1 and B2 are expressed in all cells and throughout development, whereas lamins A and C are expressed in differentiated cells, beginning at midgestation (3).Interest in the nuclear lamins has intensified with the discovery that over a dozen human diseases, including muscular dystrophy, cardiomyopathy, lipodystrophy, and progeria, are caused by mutations in LMNA (5-7). To date, more than 340 missense, nonsense, frameshift, and splicing mutations have been identified (5). In contrast, no human diseases have been linked to these types of mutations in LMNB1 and LMNB2, and, so far, the only clear-cut association between B-type lamins and disease has been the finding of LMNB1 gene duplications in autosomal-dominant leukodystrophy (8).The paucity of "lamin B diseases" is probably not due to complete redundancy of lamins B1 and B2, as Lmnb1-deficient mice are small during embryonic development and die soon after birth with defects in lungs and bones (9). Also, Lmnb1-deficient fibroblasts display misshapen cell nuclei, aneuploidy, and early senescence (9). To further examine the functional importance of the B-type lamins, we generated Lmnb2-deficient mice.

Lamin A and lamin C, both products of Lmna, are key components of the nuclear lamina. In the mouse, a deficiency in both lamin A and lamin C leads to slow growth, muscle weakness, and death by 6 weeks of age. Fibroblasts deficient in lamins A and C contain misshapen and structurally weakened nuclei, and emerin is mislocalized away from the nuclear envelope. The physiologic rationale for the existence of the 2 different Lmna products lamin A and lamin C is unclear, although several reports have suggested that lamin A may have particularly important functions, for example in the targeting of emerin and lamin C to the nuclear envelope. Here we report the development of lamin C-only mice (Lmna LCO/LCO ), which produce lamin C but no lamin A or prelamin A (the precursor to lamin A). Lmna LCO/LCO mice were entirely healthy, and Lmna LCO/LCO cells displayed normal emerin targeting and exhibited only very minimal alterations in nuclear shape and nuclear deformability. Thus, at least in the mouse, prelamin A and lamin A appear to be dispensable. Nevertheless, an accumulation of farnesyl-prelamin A (as occurs with a deficiency in the prelamin A processing enzyme Zmpste24) caused dramatically misshapen nuclei and progeria-like disease phenotypes. The apparent dispensability of prelamin A suggested that lamin A-related progeroid syndromes might be treated with impunity by reducing prelamin A synthesis. Remarkably, the presence of a single Lmna LCO allele eliminated the nuclear shape abnormalities and progeria-like disease phenotypes in Zmpste24 -/-mice. Moreover, treating Zmpste24 -/-cells with a prelamin A-specific antisense oligonucleotide reduced prelamin A levels and significantly reduced the frequency of misshapen nuclei. These studies suggest a new therapeutic strategy for treating progeria and other lamin A diseases.

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Nuclear lamins are usually classified as A-type (lamins A and C) or B-type (lamins B1 and B2). A-type lamins have been implicated in multiple genetic diseases but are not required for cell growth or development. In contrast, B-type lamins have been considered essential in eukaryotic cells, with crucial roles in DNA replication and in the formation of the mitotic spindle. Knocking down the genes for B-type lamins (LMNB1, LMNB2) in HeLa cells has been reported to cause apoptosis. In the current study, we created conditional knockout alleles for mouse Lmnb1 and Lmnb2, with the goal of testing the hypothesis that B-type lamins are crucial for the growth and viability of mammalian cells in vivo. Using the keratin 14-Cre transgene, we bred mice lacking the expression of both Lmnb1 and Lmnb2 in skin keratinocytes (Lmnb1(Δ/Δ)Lmnb2(Δ/Δ)). Lmnb1 and Lmnb2 transcripts were absent in keratinocytes of Lmnb1(Δ/Δ)Lmnb2(Δ/Δ) mice, and lamin B1 and lamin B2 proteins were undetectable. But despite an absence of B-type lamins in keratinocytes, the skin and hair of Lmnb1(Δ/Δ)Lmnb2(Δ/Δ) mice developed normally and were free of histological abnormalities, even in 2-year-old mice. After an intraperitoneal injection of bromodeoxyuridine (BrdU), similar numbers of BrdU-positive keratinocytes were observed in the skin of wild-type and Lmnb1(Δ/Δ)Lmnb2(Δ/Δ) mice. Lmnb1(Δ/Δ)Lmnb2(Δ/Δ) keratinocytes did not exhibit aneuploidy, and their growth rate was normal in culture. These studies challenge the concept that B-type lamins are essential for proliferation and vitality of eukaryotic cells.