Mammalian SAD Kinases Are Required for Neuronal Polarization

Kishi, Masashi; Pan, Y. Albert; Crump, J. Gage; Sanes, Joshua R.

doi:10.1126/science.1107403

Cited by 306 publications

(417 citation statements)

References 23 publications

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“…Interestingly, we found that the levels of SAD kinases and phosphorylated LKB1 (pLKB1) at S431, an active form of LKB1, were markedly decreased in the hippocampus or cortex of Itgb1 f/f ; Emx1-Cre mice ( Figure 4A). In line with this observation, we found that the level of phosphorylated Tau (pTau) at S262, the consensus phosphorylation site by SAD kinases [13], was decreased in these Itgb1-deletion mice ( Figure 4A). Thus, Itgb1 plays an important role in maintaining the levels or activity of , and plated onto coronal cortical slices from P0 rats.…”

Section: Itgb1 Regulation Of Neuronal Polarity Proteinssupporting

confidence: 69%

“…The upregulation of ILK may reflect homeostatic intracellular responses to the loss of Itgb1. Next, we determined states of LKB1 and SAD kinases, which are known to be essential for axon formation both in vitro and in vivo [12][13][14]. Interestingly, we found that the levels of SAD kinases and phosphorylated LKB1 (pLKB1) at S431, an active form of LKB1, were markedly decreased in the hippocampus or cortex of Itgb1 f/f ; Emx1-Cre mice ( Figure 4A).…”

Section: Itgb1 Regulation Of Neuronal Polarity Proteinsmentioning

confidence: 94%

“…Furthermore, SAD kinases are believed to mediate axon formation by regulating microtubule-associated protein Tau [3,13]. Our finding of Itgb1 regulation of SAD kinases prompted us to investigate the role of laminin/ Itgb1 signaling in regulating microtubule (MT) assembly.…”

Section: Laminin/itgb1 Signaling Promotes Mt Assembly During Axon Formentioning

confidence: 99%

“…Many cytoplasmic signaling molecules are involved in neuronal polarization and axon development [1,2,8], most of which have been identified in cultured hippocampal or cortical neurons, widely used model systems for the study of neuronal polarity [9][10][11]. Among them, several kinases, including SAD A/B and LKB1, are essential for neuronal polarization in vivo [8,[12][13][14]. In contrast, the identity of the extracellular factors that initiate neuronal polarity in vivo is just beginning to be elucidated [15,16].…”

Section: Introductionmentioning

confidence: 99%

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Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

et al. 2012

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Axon specification during neuronal polarization is closely associated with increased microtubule stabilization in one of the neurites of unpolarized neuron, but how this increased microtubule stability is achieved is unclear. Here, we show that extracellular matrix (ECM) component laminin promotes neuronal polarization via regulating directional microtubule assembly through β1 integrin (Itgb1). Contact with laminin coated on culture substrate or polystyrene beads was sufficient for axon specification of undifferentiated neurites in cultured hippocampal neurons and cortical slices. Active Itgb1 was found to be concentrated in laminin-contacting neurites. Axon formation was promoted and abolished by enhancing and attenuating Itgb1 signaling, respectively. Interestingly, laminin contact promoted plus-end microtubule assembly in a manner that required Itgb1. Moreover, stabilizing microtubules partially prevented polarization defects caused by Itgb1 downregulation. Finally, genetic ablation of Itgb1 in dorsal telencephalic progenitors caused deficits in axon development of cortical pyramidal neurons. Thus, laminin/Itgb1 signaling plays an instructive role in axon initiation and growth, both in vitro and in vivo, through the regulation of microtubule assembly. This study has established a linkage between an extrinsic factor and intrinsic cytoskeletal dynamics during neuronal polarization.

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Section: Itgb1 Regulation Of Neuronal Polarity Proteinssupporting

confidence: 69%

Section: Itgb1 Regulation Of Neuronal Polarity Proteinsmentioning

confidence: 94%

Section: Laminin/itgb1 Signaling Promotes Mt Assembly During Axon Formentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

et al. 2012

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“…76 The KIGS or KCGS motifs in the repeat domain (S262, S293, S324, S356) can be phosphorylated by MARK, PKA, PKB, SADK, CaMKII, and p70S6K. [77][78][79][80] PKA additionally phosphorylates other sites including S214, a phospho-epitope that is especially upregulated during mitosis. 81 In AD brain, tau is hyperphosphorylated at nearly all phosphorylation sites, with approximately nine phosphates per molecule, in contrast to the two to three phosphorylated residues observed in healthy control brains.…”

Section: Antiphosphorylation Strategiesmentioning

confidence: 99%

Tau-Based Treatment Strategies in Neurodegenerative Diseases

2008

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Summary:Neurofibrillary tangles are a characteristic hallmark of Alzheimer's and other neurodegenerative diseases, such as Pick's disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). These diseases are summarized as tauopathies, because neurofibrillary tangles are composed of intracellular aggregates of the microtubule-associated protein tau. The molecular mechanisms of tau-mediated neurotoxicity are not well understood; however, pathologic hyperphosphorylation and aggregation of tau play a central role in neurodegeneration and neuronal dysfunction. The present review, therefore, focuses on therapeutic approaches that aim to inhibit tau phosphorylation and aggregation or to dissolve preexisting tau aggregates. Further experimental therapy strategies include the enhancement of tau clearance by activation of proteolytic, proteasomal, or autophagosomal degradation pathways or anti-tau directed immunotherapy. Hyperphosphorylated tau does not bind microtubules, leading to microtubule instability and transport impairment. Pharmacological stabilization of microtubule networks might counteract this effect. In several tauopathies there is a shift toward four-repeat tau isoforms, and interference with the splicing machinery to decrease four-repeat splicing might be another therapeutic option.

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The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

Buchholz,

Zempel

2024

Alzheimer's & Dementia

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INTRODUCTIONAlternative splicing of the human MAPT gene generates six brain‐specific TAU isoforms. Imbalances in the TAU isoform ratio can lead to neurodegenerative diseases, underscoring the need for precise control over TAU isoform balance. Tauopathies, characterized by intracellular aggregates of hyperphosphorylated TAU, exhibit extensive neurodegeneration and can be classified by the TAU isoforms present in pathological accumulations.METHODSA comprehensive review of TAU and related dementia syndromes literature was conducted using PubMed, Google Scholar, and preprint server.RESULTSWhile TAU is recognized as key driver of neurodegeneration in specific tauopathies, the contribution of the isoforms to neuronal function and disease development remains largely elusive.DISCUSSIONIn this review we describe the role of TAU isoforms in health and disease, and stress the importance of comprehending and studying TAU isoforms in both, physiological and pathological context, in order to develop targeted therapeutic interventions for TAU‐associated diseases.Highlights MAPT splicing is tightly regulated during neuronal maturation and throughout life. TAU isoform expression is development‐, cell‐type and brain region specific. The contribution of TAU to neurodegeneration might be isoform‐specific. Ineffective TAU‐based therapies highlight the need for specific targeting strategies.

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Mammalian SAD Kinases Are Required for Neuronal Polarization

Cited by 306 publications

References 23 publications

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

Laminin/β1 integrin signal triggers axon formation by promoting microtubule assembly and stabilization

Tau-Based Treatment Strategies in Neurodegenerative Diseases

The six brain‐specific TAU isoforms and their role in Alzheimer's disease and related neurodegenerative dementia syndromes

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