Par6α signaling controls glial-guided neuronal migration

Solecki, David J.; Model, Lynn; Gaetz, Jedidiah; Kapoor, Tarun M.; Hatten, Mary E.

doi:10.1038/nn1332

Cited by 265 publications

(297 citation statements)

References 49 publications

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“…45,49 We found that PDK1 ablation reduces the amount of polymerized microtubules in the developing brain, supporting the idea that the PDK1-Akt pathway regulates locomotion at the level of microtubules. 24 Given that microtubule dynamics is regulated by microtubule-associated proteins that either stabilize or destabilize microtubules, 1,11 we sought to understand the molecular mechanisms that link Akt activation and microtubule regulation by focusing on microtubule-associated proteins.…”

Section: The Pdk1-akt Pathway Regulates Cytoplasmic Dynein/dynactin Csupporting

confidence: 76%

A balancing Akt: How to fine-tune neuronal migration speed

Itoh

2016

Neurogenesis

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In the developing mammalian neocortex, newborn neurons produced deep in the brain from neural stem/progenitor cells set out for a long journey to reach their final destination at the brain surface. This process called radial neuronal migration is prerequisite for the formation of appropriate layers and networks in the cortex, and its dysregulation has been implicated in cortical malformation and neurological diseases. Considering a fine correlation between temporal order of cortical neuronal cell types and their spatial distribution, migration speed needs to be tightly controlled to achieve correct neocortical layering, although the underlying molecular mechanisms remain not fully understood. Recently, we discovered that the kinase Akt and its activator PDK1 regulate the migration speed of mouse neocortical neurons through the cortical plate. We further found that the PDK1-Akt pathway controls coordinated movement of the nucleus and the centrosome during migration. Our data also suggested that control of neuronal migration by the PDK1-Akt pathway is mediated at the level of microtubules, possibly through regulation of the cytoplasmic dynein/ dynactin complex. Our findings thus identified a signaling pathway controlling neuronal migration speed as well as a novel link between Akt signaling and cytoplasmic dynein/dynactin complex. KEYWORDSSAkt; centrosome; dynactin; dynein; microtubule; neocortex; neuronal migration; p150; PDK1Mammalian neocortex plays important roles in higher order functions in the brain such as sensory perception, voluntary movement, and cognition. It exhibits well-organized layered structure of orderly aligned neurons of various kinds, which provides a basis for the establishment of functional neuronal connectivity. The construction of this layered structure is achieved by appropriate migration and subsequent deposition of neurons during neocortical development. 20,42 A neuron undergoes different migration modes from its initiation to termination: first, a newborn neuron that is derived and delaminates from a pseudostratified epithelial layer of neural stem/progenitor cells in the ventricular zone (VZ) has a bipolar shape; it switches to a multipolar shape as it migrates through the subventricular zone (SVZ) and the intermediate zone (IZ); eventually it regains bipolar morphology as it reaches the cortical plate (CP); it then travels toward brain surface by locomotion along a radial glial fiber(s) of neural stem/progenitor cells; and it finishes its journey on reaching the pia and by detaching from the radial glial fiber. Previous studies have revealed molecules and mechanisms controlling contiguous steps of neuronal migration as well as diseases associated with their impairment. 8,14,19,25,28,38 Importantly, there is a precise relation between the temporal order in which the various neuronal cell types are generated and their spatial distribution in the neocortex. 2,4,43,48 Also, cortical neurons utilize multiple modes of migration as described above, and each mode exhibits distinct s...

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Section: The Pdk1-akt Pathway Regulates Cytoplasmic Dynein/dynactin Csupporting

confidence: 76%

A balancing Akt: How to fine-tune neuronal migration speed

Itoh

2016

Neurogenesis

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“…Previous studies in cell culture have suggested that aPKC activity is required for cellular migration in multiple cell-types by regulating cytoskeletal remodeling (Etienne-Manneville and Hall, 2001;Etienne-Manneville and Hall, 2003;Petit et al, 2005;Sanz-Navares et al, 2001;Solecki et al, 2004). We predicted that the cell patterning phenotypes in has mutants might be due to intrinsic defects in post-mitotic cell migration.…”

Section: Retinal Migration and Cell-type Positioningmentioning

confidence: 78%

Analysis of aPKCλ and aPKCζ reveals multiple and redundant functions during vertebrate retinogenesis

Cui

Otten

Rohr

et al. 2007

Molecular and Cellular Neuroscience

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Retinal lamination is known to depend on cell polarity and localized signaling. In vertebrates, atypical Protein Kinase C proteins, aPKCλ/ι and aPKCζ, are essential for apical-basal cell polarity. However, it is not known to what extent functional redundancy has precluded a comprehensive functional characterization of aPKC signaling during vertebrate retinogenesis. Here, we show that aPKCs λ and ζ are functionally redundant for multiple aspects of retinogenesis including mitotic division location and orientation, cell-type positioning, and retinal pigment epithelial (RPE) and photoreceptor cell morphogenesis. Genetic mosaic analyses demonstrate a cell-autonomous requirement of aPKCs for RPE and photoreceptor development, and a cell-non-autonomous function that is intrinsic to the neural retina for cell-type positioning. Our observations uncover a previously unappreciated involvement of aPKCζ during zebrafish retinogenesis and suggest that aPKC signaling primes the retinal environment for appropriate cell migration of post-mitotic progenitor cells, but is not essential for correct cell-type specification.

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“…[158][159][160] This decoupling of the centrosome from the nucleus appears to be due to loss of a specific microtubule bundle known as the microtubule fork/ cage, which connects the two organelles together, 158,159 and is essential for nuclear migration. 161 Disruption of this structure and therefore nucleuscentrosome coupling may be one means by which LIS1/NDEL1 knockdown inhibits nuclear migration.…”

Section: Lis1 Ndel1 Nde1 and Disc1mentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Par6α signaling controls glial-guided neuronal migration

Cited by 265 publications

References 49 publications

A balancing Akt: How to fine-tune neuronal migration speed

A balancing Akt: How to fine-tune neuronal migration speed

Analysis of aPKCλ and aPKCζ reveals multiple and redundant functions during vertebrate retinogenesis

The DISC locus in psychiatric illness

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