Goryunov D, He CZ, Lin CS et al.Nervous-tissue-specific elimination of microtubule-actin crosslinking factor 1a results in multiple developmental defects in the mouse brain. Mol Cell Neurosci 44:1-14

Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University College of Physicians and Surgeons, NY, NY 10032, USA.
Molecular and Cellular Neuroscience (Impact Factor: 3.84). 02/2010; 44(1):1-14. DOI: 10.1016/j.mcn.2010.01.010
Source: PubMed


The microtubule-actin crosslinking factor 1 (MACF1) is a ubiquitous cytoskeletal linker protein with multiple spliced isoforms expressed in different tissues. The MACF1a isoform contains microtubule and actin-binding regions and is expressed at high levels in the nervous system. Macf1-/- mice are early embryonic lethal and hence the role of MACF1 in the nervous system could not be determined. We have specifically knocked out MACF1a in the developing mouse nervous system using Cre/loxP technology. Mutant mice died within 24-36h after birth of apparent respiratory distress. Their brains displayed a disorganized cerebral cortex with a mixed layer structure, heterotopia in the pyramidal layer of the hippocampus, disorganized thalamocortical and corticofugal fibers, and aplastic anterior and hippocampal commissures. Embryonic neurons showed a defect in traversing the cortical plate. Our data suggest a critical role for MACF1 in neuronal migration that is dependent on its ability to interact with both microfilaments and microtubules.

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Available from: Ronald K. H. Liem, Apr 16, 2015
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    • "Consistently, we found MACF1 expression in the developing cerebral cortex. A recent study reported that Tbr1-and Citp2- positive cortical layers are partially mixed in MACF1 conditional knockout brains induced by a Nestin-cre driver (Goryunov et al., 2010), suggesting a potential role of MACF1 in cortical neuron migration. However, the role of MACF1 in neuronal migration was unclear in the previous study due to the use of the Nestin-cre driver that expresses Cre recombinase in radial glial neural progenitors at E9 (Tronche et al., 1999). "
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    ABSTRACT: Neuronal migration and subsequent differentiation play critical roles for establishing functional neural circuitry in the developing brain. However, the molecular mechanisms that regulate these processes are poorly understood. Here, we show that microtubule actin crosslinking factor 1 (MACF1) determines neuronal positioning by regulating microtubule dynamics and mediating GSK-3 signaling during brain development. First, using MACF1 floxed allele mice and in utero gene manipulation, we find that MACF1 deletion suppresses migration of cortical pyramidal neurons and results in aberrant neuronal positioning in the developing brain. The cell autonomous deficit in migration is associated with abnormal dynamics of leading processes and centrosomes. Furthermore, microtubule stability is severely damaged in neurons lacking MACF1, resulting in abnormal microtubule dynamics. Finally, MACF1 interacts with and mediates GSK-3 signaling in developing neurons. Our findings establish a cellular mechanism underlying neuronal migration and provide insights into the regulation of cytoskeleton dynamics in developing neurons.
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    • "Girdin mouse mutants show hippocampal defects (see below). More recently, a conditional mouse mutant for the MT-actin crosslinking factor 1a (Macf1), that is part of the plakin family and is supposed to bridge MTs with the actin meshwork, also revealed the importance of these regulatory cross-talks, since the mutants present single-band heterotopias in the CA1-CA3 regions (Goryunov et al., 2010). Thus correct functioning of the actin cytoskeleton seems clearly also critical for hippocampal cell migration. "
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    ABSTRACT: In this review, we focus on CA3 neuronal migration disorders in the rodent. We begin by introducing the main steps of hippocampal development, and we summarize characteristic hippocampal malformations in human. We then describe various mouse mutants showing structural hippocampal defects. Notably, genes identified in human cortical neuronal migration disorders consistently give rise to a CA3 phenotype when mutated in the mouse. We successively describe their molecular, physiological and behavioral phenotypes that together contribute to a better understanding of CA3-dependent functions. We finally discuss potential factors underlying the CA3 vulnerability revealed by these mouse mutants and that may also contribute to other human neurological and psychiatric disorders.
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    • "F10 had fetal akinesia syndrome probably caused by neuroaxonal dystrophy. We found the compound heterozygous mutations c.5323G>A (p.1775E>K) and c.8626A>G (p.2876I>V) in MACF1 (MIM 608271, ENST00000372925), which encodes cytoskeletal protein microtubule-actin cross-linking factor 1. Knockout of the mouse orthologue causes defects in axonal extension (31). Finally, F13 had multiple abnormalities including a multicystic-dysplastic kidney, distorted ribs and spine, brain defects and bilateral talipes equinovarus. "
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