PDK1–Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex

Itoh, Yoshio; Higuchi, Masakazu; Oishi, Koji; Kishi, Yusuke; Okazaki, Tomohiko; Sakai, Hiroshi; Miyata, Takaki; Nakajima, Kazunori; Gotoh, Yukiko

doi:10.1073/pnas.1516321113

Cited by 41 publications

(40 citation statements)

References 61 publications

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“…Inhibition or activation of the PDK1-Akt pathway changed the locomotion speed by 20 to 30%, 24 but did not abrogate migration altogether. It is assumed that changing the speed of neuronal migration in entire neuronal population will not affect layer structure.…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 90%

“…12,17,31 To circumvent these limitations, we conditionally knocked out PDK1 either in the central nervous system or in postmitotic cortical neurons. 24 Both mutant brains showed disorganized layer structure in the neocortex, implying migration defects. BrdU birthdating analysis and live-imaging of neuronal migration in organotypic brain slice culture revealed that PDK1 deletion slows down locomotion within the CP in both mutant brains, demonstrating that PDK1 is required for an appropriate speed of bipolar locomotion.…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

“…24 The PDK1-Akt axis acts downstream of phosphoinositide 3-kinase (PI3K), which in turn is activated by various…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

“…24 The PDK1-Akt axis acts downstream of phosphoinositide 3-kinase (PI3K), which in turn is activated by various extracellular stimuli, and plays key roles in many biological processes including microtubule stabilization, cell polarization and cell migration. 5,50 PI3K activity is required for normal radial migration in the neocortex, 6,29 but the contribution of the PDK1-Akt pathway to neuronal locomotion has remained elusive, in part because of functional redundancy among the 3 Akt family members and the early lethality of Akt and PDK1 mutant mice.…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

“…Also, a recent study showed the evidence of a positioning-dependent layer identity acquisition, 39 suggesting that minor change in migration speed could potentially be accommodated by the post-migratory environment. However, while deep-layer neurons were positioned normally, upper-layer neurons showed layering defect in PDK1 mutant mouse brains, 24 strongly arguing that precise regulation of migration speed is indeed indispensable for the construction of appropriate layer structure. Upper-layer specific defect also implies that neurons migrating longer distances are more vulnerable to changes in migration speed.…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

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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: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 90%

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

“…24 The PDK1-Akt axis acts downstream of phosphoinositide 3-kinase (PI3K), which in turn is activated by various…”

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

Section: Regulation Of Locomotion Speed By the Pdk1-akt Pathwaymentioning

confidence: 99%

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

Itoh

2016

Neurogenesis

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FGF signaling is required for chemokinesis and ventral migration of trunk neural crest cells

Dunkel

Chaverra

Bradley

et al. 2020

Developmental Dynamics

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Background Neural crest cells (NCCs) delaminate from the neural tube (NT) and migrate ventrally to generate the trunk peripheral nervous system (PNS). Although several signaling pathways have been identified that steer NCCs once they are on their ventral trajectory, no molecules have been identified that are required for the initial migration between the NT and the dorsal root ganglion. Given the critical role of fibroblast growth factor (FGF) signaling in embryogenesis, we investigated its function in this initial migration. Results FGFR1 signaling is required for the migration of newly delaminated NCCs onto the ventral pathway. Live imaging of migrating NCCs revealed that inhibition of FGFR1 signaling caused the dorsally stalled NCCs to lose their dorsal/ventral oriented polarity and instead adopt a rounded morphology while dynamically extending filopodia. FGF8, an FGFR1 ligand, increased motility of NCCs away from the NT by acting chemokinetically. Finally, we provide evidence that inhibition of FGFR1‐mediated chemokinesis is partially rescued by increasing Akt signaling, inhibiting RhoA, and activation of N‐cadherin signaling. Conclusion These data support a model in which NCCs are stimulated chemokinetically by FGF:FGFR1 signaling, and that this activation positions and orients NCCs on their ventral migratory route—a process that is essential for patterning the trunk PNS.

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Microtubules: From understanding their dynamics to using them as potential therapeutic targets

Ilan

2018

Journal Cellular Physiology

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Microtubules (MT) and actin microfilaments are dynamic cytoskeleton components involved in a range of intracellular processes. MTs play a role in cell division, beating of cilia and flagella, and intracellular transport. Over the past decades, much knowledge has been gained regarding MT function and structure, and its role in underlying disease progression. This makes MT potential therapeutic targets for various disorders. Disturbances in MT and their associated proteins are the underlying cause of diseases such as Alzheimer’s disease, cancer, and several genetic diseases. Some of the advances in the field of MT research, as well as the potenti G beta gamma, is needed al uses of MT‐targeting agents in various conditions have been reviewed here.

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PDK1–Akt pathway regulates radial neuronal migration and microtubules in the developing mouse neocortex

Cited by 41 publications

References 61 publications

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

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

FGF signaling is required for chemokinesis and ventral migration of trunk neural crest cells

Microtubules: From understanding their dynamics to using them as potential therapeutic targets

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