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WIREs Dev Biol
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Cytoskeleton in action: lissencephaly, a neuronal migration disorder

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Abstract During neocortical development, the extensive migratory movements of neurons from their place of birth to their final location are essential for the coordinated wiring of synaptic circuits and proper neurological function. Failure or delay in neuronal migration causes severe abnormalities in cortical layering, which consequently results in human lissencephaly (‘smooth brain’), a neuronal migration disorder. The brains of lissencephaly patients have less‐convoluted gyri in the cerebral cortex with impaired cortical lamination of neurons. Since microtubule (MT) and actin‐associated proteins play important functions in regulating the dynamics of MT and actin cytoskeletons during neuronal migration, genetic mutations or deletions of crucial genes involved in cytoskeletal processes lead to lissencephaly in human and neuronal migration defects in mouse. During neuronal migration, MT organization and transport are controlled by platelet‐activating factor acetylhydrolase isoform 1b regulatory subunit 1 (PAFAH1B1, formerly known as LIS1, Lissencephaly‐1), doublecortin (DCX), YWHAE, and tubulin. Actin stress fibers are modulated by PAFAH1B1 (LIS1), DCX, RELN, and VLDLR (very low‐density lipoprotein receptor)/LRP8 (low‐density lipoprotein‐related receptor 8, formerly known as APOER2). There are several important levels of crosstalk between these two cytoskeletal systems to establish accurate cortical patterning in development. The recent understanding of the protein networks that govern neuronal migration by regulating cytoskeletal dynamics, from human and mouse genetics as well as molecular and cellular analyses, provides new insights on neuronal migration disorders and may help us devise novel therapeutic strategies for such brain malformations. WIREs Dev Biol 2013, 2:229–245. doi: 10.1002/wdev.67 This article is categorized under: Nervous System Development > Vertebrates: General Principles Nervous System Development > Vertebrates: Regional Development Birth Defects > Craniofacial and Nervous System Anomalies

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Schematic representation of the developing mammalian brain. In the coronal section of one half of the mammalian developing forebrain there are two main migratory streams of postmitotic neurons: the radial migration of excitatory cortical pyramidal neurons from the ventricular zone (VZ) to the cortical plate (CP) (black arrow) and the tangential migration of inhibitory GABAergic interneurons from lateral and medial‐ganglionic eminences (LGE/MGE) into the neocortex (blue arrow). The developing cerebral cortex in mammals is multilayered with different neuronal cell populations. Near the lateral ventricle (LV) surface, neural progenitors (NPs) reside in the ventricular zone (VZ). This progenitor zone is extended to subventricular and intermediate zones (SVZ and IZ, respectively). Newly born neurons from the division of NPs undergo extensive radial neuronal migration to enter the cortical plate (CP). The marginal zone (MZ) is the most superficial layer to contain Cajal‐Retzius cells secreting the RELN (Reelin) glycoprotein.

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Cyclin‐dependent kinase 5 (CDK5) phosphorylation substrates during neuronal migration. When CDK5 is activated by binding of CDK5R1 (p35)/ CDK5R2 (p39), this kinase phosphorylates multiple substrates in migrating neurons. Among those substrates, doublecortin (DCX), Nuclear distribution gene E homolog 1 (NDEL1), microtubule‐associated protein 1b (MTAP1B), and protein tyrosine kinase 2 (PTK2, also called FAK) are microtubule (MT)‐regulating proteins. A very interesting phosphorylation substrate of CDK5 is CDKN1B (p27kip1). P‐CDKN1B suppresses RhoA GTPase activity. RhoA–ROCK–LIM‐domain containing protein kinase 1 (LIMK1)–CFL1 and RhoA–ROCK–MLC (myosin light chain) signaling pathway have been implicated in actin cytoskeletal remodeling during neuronal migration. CDK5 indirectly affects these actin‐regulating signaling pathways by modulating CDK5N1B function. (Blue proteins, MT regulators; red proteins, actin regulators).

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Platelet‐activating factor acetylhydrolase 1 regulatory subnuit 1 (PAFAH1B1) and RELN (Reelin)‐mediated actin regulation. Formation of the PAFAH1B1‐CLIP1‐IQGAP1‐CDC42/RAC1 complex stabilizes and sustains the GTPase activities of CDC42 and RAC1. RELN, a large glycoprotein secreted from the marginal zone (MZ) area in the cortex, directly binds to lipoprotein receptors such as very low‐density lipoprotein receptor (VLDLR) and low‐density lipoprotein‐related receptor 8 (LRP8) (APOER2). This binding recruits the disabled homolog 1 (DAB1) adaptor protein to the membrane where DAB1 is phosphorylated. P‐DAB1 activates PI3K‐LIM‐domain containing protein kinase 1 (LIMK1) signaling and LIMK1 phoshorylates CFL1 (cofilin), an actin‐severing protein, which keeps CFL1 in an inactive state. This further stabilizes F‐actin stress fibers in migrating neurons. Since the dynamic regulation of the actin cytoskeleton is required for neuronal motility, a balance between actin polymerization and depolymerization is essential for neuronal migration processes. (Dashed line, direct interaction between PAFAH1B1 and P‐DAB1; blue protein, microtubule (MT) regulator; red proteins, actin regulators).

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Nuclear distribution gene E homolog 1 (NDE1) and NDE1‐like (NDEL1) are key proteins integrating several signals in neuronal migration. NDE1 and NDEL1 are two mammalian homologues of Aspergillus nidulans nudE. Upon cyclin‐dependent kinase 5 (CDK5)‐mediated phosphorylation of NDEL1, P‐NDEL1 binds to YWHAE (formerly known as 14‐3‐3 ε). Isolated lissencephaly sequence (ILS) is caused by the haploinsufficiency of human PAFAH1B1 (LIS1) gene. Simultaneous chromosomal deletion of the regions including YWHAE and PAFAH1B1 in human causes Miller–Dieker syndrome (MDS), a severe case of lissencephaly with craniofacial malformation. Human NDE1 heterozygous mutations result in micro‐lissencephaly.

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Cytoskeletal features of migrating neurons during central nervous system (CNS) development. Migrating neurons are polarized from the growth cone, which is the migrating tip of the leading process (LP) to the trailing process (TP). The nucleus is surrounded by a perinuclear tubulin cage and the rear side of the nucleus is enriched with actomyosin (filamentous actin, F‐actin + Myosin‐II) that generates pushing forces of nuclear movement (somal translocation, nucleokinesis). Migration occurs in two distinct modes of movements in a two‐stroke model: (1) centrosome (C) movement toward the swelling in the LP and (2) nuclear (N) movement in the direction of migration. This N–C coupling consequently provides the pulling force on microtubules (MTs) along the LP, which establishes new contacts to adhesion substrates.

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PAFAH1B1 (platelet‐activating factor acetylhydrolase 1 regulatory subnuit 1, formerly known as LIS1)‐binding partners. The binding of PAFAH1B1 (LIS1) to the cytoplasmic dynein/dynactin complex is evolutionarily conserved from fungi to mammals. Nuclear distribution proteins such as nuclear distribution gene E homolog 1 (NDE1), NDE1‐like (NDEL1), and nuclear distribution gene C homolog (NUDC) interact directly with PAFAH1B1. PAFAH1B1 itself is a microtubule‐associated protein (MAP) and is localized at tubulin/microtubule (MT)‐rich subcellular compartments in cells like centrosomes. Other MAPs, such as doublecortin (DCX) and microtubule‐associated protein 1b (MTAP1B), are also PAFAH1B1‐binding partners. PAFAH1B1 was also identified as a noncatalytic subunit of PAFAH and PAFAH1B1 associates with PAFAH catalytic subunits such as PAFAH1B2 (PAFAH α 2) and PAFAH1B3 (PAFAH α 1). When PAFAH1B1 binds to CLIP1 (CLIP170), a MT plus end protein, it forms a complex with IQGAP1 and CDC42/RAC1. Through this interaction, PAFAH1B1 participates in F‐actin dynamics in growth cones during neuronal migration. Interestingly, PAFAH1B1 also binds to disabled homolog 1 (DAB1), an actin‐regulatory protein acting in RELN (Reelin) signaling pathway. PAFAH1B1 has dual roles in distinct regulatory pathways of MT and actin cytoskeletons. (Blue proteins, MT regulators; red proteins, actin regulators; green proteins, unclear detailed function in MT/actin regulation).

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