The cellular roles of the lissencephaly gene LIS1, and what they tell us aboutbrain development

Vallee, Richard B.; Tsai, Jin Wu

doi:10.1101/gad.1417206

Cited by 144 publications

(139 citation statements)

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“…In WT embryos, Ctip2 staining was detected in the upper part of the FoxP2 territory, corresponding to layer V, whereas in Lmnb2 −/− embryos the two cell populations were intermixed. LIS1, NDE1, and NDEL1 have been shown to regulate the dynein motors required for nuclear translocation along microtubules (24,25), and knockouts or knockdowns of these proteins result in impaired neuronal migration (12). In humans, LIS1 mutations are the most common cause of defective neuronal migration and lissencephaly (19,20).…”

Section: Discussionmentioning

confidence: 99%

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Coffinier¹,

Chang²,

Nobumori³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

209

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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.

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Section: Discussionmentioning

confidence: 99%

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Coffinier¹,

Chang²,

Nobumori³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

145

209

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“…In the hyphae, endosomes are moved to the hyphal apex by kinesin-3, where they are loaded onto dynein motors for reverse movement 76 . Uploading of endosomes onto dynein is dependent on dynactin and LIS1 (a dynein activator that is defective in patients with the brain disorder lissencephaly 77,78 ), which both accumulate at microtubule plus ends. The functional significance of bidirectional endosome movement needs to be clarified, but it might be either to keep these organelles dispersed in the cytoplasm 79 , to enhance encounters between different compartments for subsequent fusion 68 , or to support fission 61 .…”

Section: Box 2 | Modes Of Motor-cargo Associationmentioning

confidence: 99%

Powering membrane traffic in endocytosis and recycling

Soldati

Schliwa

2006

Nat Rev Mol Cell Biol

312

279

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| Early in evolution, the diversification of membrane-bound compartments that characterize eukaryotic cells was accompanied by the elaboration of molecular machineries that mediate intercompartmental communication and deliver materials to specific destinations. Molecular motors that move on tracks of actin filaments or microtubules mediate the movement of organelles and transport between compartments. The subjects of this review are the motors that power the transport steps along the endocytic and recycling pathways, their modes of attachment to cargo and their regulation.The emergence of eukaryotic cells was accompanied by the development of endomembrane systems that compartmentalize biochemical pathways and biosynthetic processes. An evolutionary trend towards increasing complexity and subcellular specialization necessitated the development of machineries for intercompartmental communication. Molecular assemblies evolved to confer specificity to the interactions of donor and acceptor compartments (budding, sorting, tethering and fusion). Cytoskeletal polymers such as actin filaments and microtubules, which help segregate genetic material and determine cell shape and subcellular architecture, were co-opted as tracks for transport. In animal cells, microtubules support long-range transport, whereas the more flexible actin filaments serve short-range movements both near the cell periphery and in the cell interior. Also, actin filaments can be woven into dense networks of short fibres through the action of crosslinkers and branchpromoting complexes. On the other hand, in many plant cells, bundled actin filaments can form extended tracks for long-distance transport. Owing to the gel-like nature of the cytoplasm, the Brownian movement of organelles is severely restricted and cargoes have to be transported to their destinations at the expense of energy. Furthermore, seemingly random, but motor-dependent, movement is proposed to increase the probability of vesicle collisions and therefore promote fusion events. Movement is powered by three ATP-dependent motors: myosin, kinesin and dynein. Over the course of eukaryotic evolution, these motors have diversified into a large number of families with specific tasks (FIG. 1).Here, we review the involvement of molecular motors in the movement of endosomes and in vesicular trafficking along the endocytic and recycling pathways. These pathways are summarized in FIG. 2. We do not, however,

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“…The connection between LIS1 homologs and cytoplasmic dynein was first made in the filamentous fungus Aspergillus nidulans and the budding yeast Saccharomyces cerevisiae by genetic studies (Xiang et al 1995a;Geiser et al 1997). Further studies have demonstrated that LIS1 and its homologs in higher eukaryotic systems are also involved in cytoplasmic dynein function, and physical interactions between LIS1 and dynein/dynactin have been shown (Liu et al 2000;Sasaki et al 2000;Dawe et al 2001;Tai et al 2002;reviewed by Wynshaw-Boris and Gambello 2001;Gupta et al 2002;Tsai and Gleeson 2005;Vallee and Tsai 2006). Recently, purified LIS1 has been shown to enhance the microtubule-stimulated ATPase activity of the dynein motor (Mesngon et al 2006).…”

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confidence: 99%

Point Mutations in the Stem Region and the Fourth AAA Domain of Cytoplasmic Dynein Heavy Chain Partially Suppress the Phenotype of NUDF/LIS1 Loss in Aspergillus nidulans

Zhuang

Zhang²,

Xiang

2007

Genetics

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Cytoplasmic dynein performs multiple cellular tasks but its regulation remains unclear. The dynein heavy chain has a N-terminal stem that binds to other subunits and a C-terminal motor unit that contains six AAA (ATPase associated with cellular activities) domains and a microtubule-binding site located between AAA4 and AAA5. In Aspergillus nidulans, NUDF (a LIS1 homolog) functions in the dynein pathway, and two nudF6 partial suppressors were mapped to the nudA dynein heavy chain locus. Here we identified these two mutations. The nudAL1098F mutation resides in the stem region, and nudAR3086C is in the end of AAA4. These mutations partially suppress the phenotype of nudF deletion but do not suppress the phenotype exhibited by mutants of dynein intermediate chain and Arp1. Surprisingly, the stronger DnudF suppressor, nudAR3086C, causes an obvious decrease in the basal level of dynein's ATPase activity and an increase in dynein's distribution along microtubules. Thus, suppression of the DnudF phenotype may result from mechanisms other than simply the enhancement of dynein's ATPase activity. The fact that a mutation in the end of AAA4 negatively regulates dynein's ATPase activity but partially compensates for NUDF loss indicates the importance of the AAA4 domain in dynein regulation in vivo.

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The cellular roles of the lissencephaly gene LIS1, and what they tell us aboutbrain development

Cited by 144 publications

References 65 publications

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Abnormal development of the cerebral cortex and cerebellum in the setting of lamin B2 deficiency

Powering membrane traffic in endocytosis and recycling

Point Mutations in the Stem Region and the Fourth AAA Domain of Cytoplasmic Dynein Heavy Chain Partially Suppress the Phenotype of NUDF/LIS1 Loss in Aspergillus nidulans

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