Nuclear lamins and brain development* Stephen G. Young 1,2,* , Hea-Jin Jung 3 , Catherine Coffinier 1 , and Loren G. Fong 1,* Departments of 1 Medicine and 2 Human Genetics and the 3 Molecular Biology Institute, University of California, Los Angeles, CA 90095, USA Running title: Function of nuclear lamins in the brain † Address correspondence to: Stephen G. Young or Loren G. Fong, 695 Charles E. Young Dr. South, Los Angeles, CA 90095. Tel: 310-825-4422; Fax: 310-206-0865; E-mails: sgyoung@mednet.ucla.edu, lfong@mednet.ucla.edu Keywords: nuclear envelope, nuclear lamina, lamin B1, lamin B2, prelamin A, lamin C _____________________________________________________________________________________ SUMMARY The nuclear lamina is composed mainly of lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins). Dogma has held that lamins B1 and B2 play unique and essential roles in the nucleus of every eukaryotic cell. Recent studies have raised doubts about that view but have uncovered crucial roles for lamins B1 and B2 in neuronal migration during the development of the brain. The relevance of lamins A and C in the brain remains unclear, but it is intriguing that prelamin A expression in the brain is low and is regulated by miR-9, a brain-specific microRNA. The nuclear lamina, an intermediate filament meshwork lying beneath the inner nuclear membrane, consists mainly of four proteins, lamins A, C, B1, and B2. Prelamin A (the precursor to mature lamin A) and lamin C are alternatively spliced products of LMNA (1), while lamins B1 and B2 are products of independent genes, LMNB1 and LMNB2 (2,3). The nuclear lamina provides a structural support for the cell nucleus and interacts with both the chromatin and inner nuclear membrane proteins. Those functions—and the association of the nuclear lamina with disease—have been covered in other reviews (4-11). This review will focus on a pair of new discoveries on the biology of nuclear lamins. The first is that the B-type lamins are critical for neuronal migration in the developing brain (12-14); the second is that the expression of lamin A is negligible in the mouse brain and that lamin A expression is regulated by miR-9, a brain-specific microRNA (15). The B-type lamins The B-type lamins, lamins B1 and B2, are expressed in nearly every cell type, starting at the earliest stages of development, and for that reason alone, they have been considered fundamental constituents of the nuclear lamina (6). This view has been supported by two arguments. First, RNAi inhibition of LMNB1 1 and LMNB2 expression in HeLa cells has been reported to arrest cell growth and lead to apoptosis, while knocking down LMNA expression had no such effects (16). Second, many papers have linked B-type lamins to crucial functions in the cell nucleus. For example, electron microscopy studies of B-type lamin localization in cultured cells (17) suggested that these lamins were important for heterochromatin organization. Another group used a dominant- negative lamin B1 mutant to show that B-type lamins are crucial in the organization of the mitotic spindle (18). Others have suggested vital roles for B-type lamins in DNA replication (19), gene transcription (20,21), the formation of nucleoli (22), responses to oxidative stress (23), positioning of chromosomes during interphase (24), and in regulating the cell cycle (25). The welter of reports suggesting unique and crucial functions for B-type lamins in the cell nucleus almost certainly waylaid enthusiasm for generating knockout mouse models. However, in 2004, Vergnes et al. (26) created a Lmnb1- deficient mouse (Lmnb1 Δ/Δ ) with a gene-trap ES cell clone (27) that yielded a lamin B1–βgeo fusion protein (26). This fusion lacked crucial domains of the lamin B1 protein (26) and was clearly nonfunctional. Lmnb1 Δ/Δ embryos survived development but were small and died shortly after birth with evidence of immature lungs, abnormalities in several bones, and a misshapen http://www.jbc.org/cgi/doi/10.1074/jbc.R112.354407 The latest version is at JBC Papers in Press. Published on March 13, 2012 as Manuscript R112.354407 Copyright 2012 by The American Society for Biochemistry and Molecular Biology, Inc. by guest on July 24, 2017 http://www.jbc.org/ Downloaded from