Nuclear envelope and lamin B2 function in the central nervous system

The nuclear envelope (NE) embraces the genome with a rich tapestry of outer and inner membrane proteins, some of which mechanically link the cytoskeleton to the nucleoskeleton (1). The nucleoskeleton includes the nuclear intermediate filaments, formed by independent networks of A- and B-type lamins. Humans have one gene (LMNA) encoding A-type lamins and two genes encoding B-type lamins (LMNB1 and LMNB2) (2). Fascinating links to human physiology have emerged as mutations in LMNA were found to cause a spectrum of disorders, generally termed “laminopathies.” Most known laminopathies affect one or more specific “load-bearing” tissues, with clinical phenotypes that include muscular dystrophy, cardiomyopathy, skin or bone defects, or widespread connective tissue defects that lead to segmental progeroid (“accelerated aging”) syndromes (3). Certain mutations in LMNA can even cause lipodystrophy and diabetes, or Charcot-Marie-Tooth axonal neuropathy. However, the central nervous system was conspicuously and puzzlingly unaffected, even in LMNA knockout mice. A new report in a recent issue of PNAS (4) fills this major gap in knowledge by showing that lamin B2 knockout mice have grossly abnormal development of the cerebral cortex and cerebellum.

Lamins A, B1, and B2 show complex and differential patterns of expression in developing neurogenic regions of the rat brain (5). Lamins B1 and B2 are each expressed at the highest levels in different neuronal cell types, suggesting both overlapping and potentially unique roles during brain development (5). Neuronal functions for B-type lamins were first seen in Drosophila, which has one A-type lamin and one B-type lamin; mutating the B-type lamin disrupted the developmentally regulated migration of nuclei within photoreceptor cells (6). Mice deficient in lamin B1 die soon after birth with multiple phenotypes including lung and bone defects (7). The new study by Coffinier et al. (4) shows that lamin B2 knockout mice have severe defects in the layering of neurons in the cerebral cortex and cerebellum. This phenotype, known as lissencephaly, is due to defective migration of nuclei within developing lamin B2-deficient mouse neurons. Thus, lamin B2 is a crucial nucleoskeletal component of the nuclear migration machinery in mammals, along with the NE-spanning LINC complexes formed by SUN-domain proteins and Syne/Nesprin proteins (8, 9). Lamin B2 now provides the molecular “platform” needed for researchers to identify the other NE and intranuclear proteins that interact functionally with lamin B2 during nuclear migration, and map new genes relevant to lissencephaly.

Genetic Basis for a Wide Spectrum of Brain Disorders?

The Coffinier et al. study (4) has another, farther-reaching, implication for human physiology: in addition to lissencephaly, a profoundly devastating condition, is the possibility that relatively minor mutations in lamin B2 might disrupt many subtle aspects of brain development or brain function. Ample precedent for this sweeping statement is provided by LMNA. Nearly all known LMNA-associated human laminopathies are caused by single amino acid changes (“missense” mutations) in A-type lamin proteins; most of these mutations are dominant but show variable penetrance, consistent with growing numbers of interacting genes and proteins, and the recognition that NE proteins have major roles in signaling (10, 11).

Relatively minor mutations in lamin B2 might disrupt many subtle aspects of brain development.

One can now imagine many ways in which brain development, higher-order brain function, or cognition might be subtly perturbed by “minor” mutations in LMNB2. Furthermore, because lamin B1 and lamin B2 are each expressed at high levels in different neurogenic regions of the brain (5), one can speculate that a distinct spectrum of “brain laminopathies” might eventually be mapped to missense mutations in LMNB1. Indeed, a simple duplication of the LMNB1 gene, which increases the level of wild-type lamin B1 protein, causes autosomal dominant leukodystrophy, a slowly progressive adult-onset disorder involving symmetrical loss of myelin in the central nervous system (12). The nature of any brain disorders that might be caused by “subtle” mutations in lamin B1 or lamin B2 is, of course, unknown.

An Expanding Spectrum of “Brain Laminopathies”

Finally, one hopes that the emergence of brain laminopathies will stimulate basic studies to learn more about the molecular functions of lamin B2, and especially to identify NE and intranuclear proteins that bind selectively to lamin B2. Few such proteins are known in the brain or any tissue. Identification of these proteins will be important to understand how nuclear structure contributes to neuronal development and function, and also because mutations in functionally relevant partners might cause related clinical phenotypes. For example, one laminopathy, Emery-Dreifuss muscular dystrophy, is caused by mutations in at least four different genes (LMNA, SYNE-1, SYNE-2 and EMR, encoding the NE membrane protein emerin) that collaborate to form mechanosensitive NE-spanning LINC complexes in muscle cells (9, 13). However, other mutations in SYNE-1, which encodes multiple nesprin-1 protein isoforms, are known to cause pure cerebellar ataxia and cerebellar atrophy (lissencephaly) in humans (14).

Much work remains in order to understand how B-type lamins, and their binding partners, contribute to the development and function of the brain. Current limited evidence provides only glimpses of this involvement. For example, a conserved lamin B-binding protein named BAF (barrier to autointegration factor) binds and regulates two proteins, Crx and Nemp1, required for neuronal (retinal) development (15, 16). Another example is LAP1 (lamina associated polypeptide 1), a lamin A- and lamin B-binding NE membrane protein that interacts via its luminal domain with torsinA, mutations in which cause autosomal dominant primary dystonia, a movement disorder of the central nervous system (17). Further explorations of lamin B2 function, especially in the diverse cell types that comprise the mind, will help solve one of the last “great unknowns” of cell biology: how the genome is organized, regulated, and influenced by nuclear structure.