Impaired macroglial development and axonal conductivity contributes to the neuropathology of DYRK1A-related intellectual disability syndrome

  • Lord, C. et al. Autism spectrum disorder. Lancet 392(10146), 508–520 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515(7526), 216–221 (2014).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Yuen, R. et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat. Neurosci. 20(4), 602–611 (2017).

    Article 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Stessman, H. A. et al. Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases. Nat. Genet. 49(4), 515–526 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180(3), 568-584 e23 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155(5), 997–1007 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155(5), 1008–1021 (2013).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515(7526), 209–215 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • O’Roak, B. J. et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 338(6114), 1619–1622 (2012).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • van Bon, B. W. et al. Disruptive de novo mutations of DYRK1A lead to a syndromic form of autism and ID. Mol. Psychiatry 21(1), 126–132 (2016).

    Article 
    PubMed 

    Google Scholar
     

  • Evers, J. M. et al. Structural analysis of pathogenic mutations in the DYRK1A gene in patients with developmental disorders. Hum. Mol. Genet. 26(3), 519–526 (2017).

    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Arranz, J. et al. Impaired development of neocortical circuits contributes to the neurological alterations in DYRK1A haploinsufficiency syndrome. Neurobiol. Dis. 127, 210–222 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Moller, R. S. et al. Truncation of the Down syndrome candidate gene DYRK1A in two unrelated patients with microcephaly. Am. J. Hum. Genet. 82(5), 1165–1170 (2008).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • van Bon, B. W. et al. Intragenic deletion in DYRK1A leads to mental retardation and primary microcephaly. Clin. Genet. 79(3), 296–299 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Courcet, J. B. et al. The DYRK1A gene is a cause of syndromic intellectual disability with severe microcephaly and epilepsy. J. Med. Genet. 49(12), 731–736 (2012).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Ji, J. et al. DYRK1A haploinsufficiency causes a new recognizable syndrome with microcephaly, intellectual disability, speech impairment, and distinct facies. Eur. J. Hum. Genet. 23(11), 1473–1481 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Earl, R. K. et al. Clinical phenotype of ASD-associated DYRK1A haploinsufficiency. Mol. Autism 8, 54 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Fenster, R. et al. Characterization of phenotypic range in DYRK1A haploinsufficiency syndrome using standardized behavioral measures. Am. J. Med. Genet. A 5, 22 (2022).


    Google Scholar
     

  • Hanly, C. et al. Description of neurodevelopmental phenotypes associated with 10 genetic neurodevelopmental disorders: A scoping review. Clin. Genet. 99(3), 335–346 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Becker, W. & Sippl, W. Activation, regulation, and inhibition of DYRK1A. FEBS J. 278(2), 246–256 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Aranda, S., Laguna, A. & de la Luna, S. DYRK family of protein kinases: Evolutionary relationships, biochemical properties, and functional roles. FASEB J. 25(2), 449–462 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Arbones, M. L. et al. DYRK1A and cognition: A lifelong relationship. Pharmacol. Ther. 194, 199–221 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tejedor, F. J. & Hammerle, B. MNB/DYRK1A as a multiple regulator of neuronal development. FEBS J. 278(2), 223–235 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Fotaki, V. et al. Dyrk1A haploinsufficiency affects viability and causes developmental delay and abnormal brain morphology in mice. Mol. Cell Biol. 22(18), 6636–6647 (2002).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Arque, G. et al. Impaired spatial learning strategies and novel object recognition in mice haploinsufficient for the dual specificity tyrosine-regulated kinase-1A (Dyrk1A). PLoS ONE 3(7), e2575 (2008).

    Article 
    ADS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Raveau, M. et al. DYRK1A-haploinsufficiency in mice causes autistic-like features and febrile seizures. Neurobiol. Dis. 110, 180–191 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Najas, S. et al. DYRK1A-mediated cyclin D1 degradation in neural stem cells contributes to the neurogenic cortical defects in down syndrome. EBioMedicine 2(2), 120–134 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Benavides-Piccione, R. et al. Alterations in the phenotype of neocortical pyramidal cells in the Dyrk1A+/− mouse. Neurobiol. Dis. 20(1), 115–122 (2005).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Allen, N. J. & Lyons, D. A. Glia as architects of central nervous system formation and function. Science 362(6411), 181–185 (2018).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zeidan-Chulia, F. et al. The glial perspective of autism spectrum disorders. Neurosci. Biobehav. Rev. 38, 160–172 (2014).

    Article 
    PubMed 

    Google Scholar
     

  • Sloan, S. A. & Barres, B. A. Mechanisms of astrocyte development and their contributions to neurodevelopmental disorders. Curr. Opin. Neurobiol. 27, 75–81 (2014).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Phan, B. N. et al. A myelin-related transcriptomic profile is shared by Pitt-Hopkins syndrome models and human autism spectrum disorder. Nat. Neurosci. 23(3), 375–385 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Miller, F. D. & Gauthier, A. S. Timing is everything: Making neurons versus glia in the developing cortex. Neuron 54(3), 357–369 (2007).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kriegstein, A. & Alvarez-Buylla, A. The glial nature of embryonic and adult neural stem cells. Annu. Rev. Neurosci. 32, 149–184 (2009).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Bergles, D. E. & Richardson, W. D. Oligodendrocyte Development and Plasticity. Cold Spring Harb Perspect. Biol. 8(2), a020453 (2015).

    Article 
    PubMed 

    Google Scholar
     

  • Guedj, F. et al. DYRK1A: A master regulatory protein controlling brain growth. Neurobiol. Dis. 46(1), 190–203 (2012).

    Article 
    MathSciNet 
    PubMed 
    CAS 

    Google Scholar
     

  • Ge, W. P. et al. Local generation of glia is a major astrocyte source in postnatal cortex. Nature 484(7394), 376–380 (2012).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Fernandez-Martinez, J. et al. Attenuation of Notch signalling by the Down-syndrome-associated kinase DYRK1A. J. Cell Sci. 122(Pt 10), 1574–1583 (2009).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kurabayashi, N., Nguyen, M. D. & Sanada, K. DYRK1A overexpression enhances STAT activity and astrogliogenesis in a Down syndrome mouse model. EMBO Rep. 16(11), 1548–1562 (2015).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Hutton, S. R. & Pevny, L. H. SOX2 expression levels distinguish between neural progenitor populations of the developing dorsal telencephalon. Dev. Biol. 352(1), 40–47 (2011).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sofroniew, M. V. & Vinters, H. V. Astrocytes: biology and pathology. Acta Neuropathol 119(1), 7–35 (2010).

    Article 
    PubMed 

    Google Scholar
     

  • Sun, W. et al. SOX9 is an astrocyte-specific nuclear marker in the adult brain outside the neurogenic regions. J. Neurosci. 37(17), 4493–4507 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Ito, D. et al. Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res. Mol. Brain Res. 57(1), 1–9 (1998).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kessaris, N. et al. Competing waves of oligodendrocytes in the forebrain and postnatal elimination of an embryonic lineage. Nat. Neurosci. 9(2), 173–179 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Polioudakis, D. et al. A single-cell transcriptomic atlas of human neocortical development during mid-gestation. Neuron 103(5), 785-801 e8 (2019).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zhang, Y. et al. Purification and characterization of progenitor and mature human astrocytes reveals transcriptional and functional differences with mouse. Neuron 89(1), 37–53 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Pringle, N. P. & Richardson, W. D. A singularity of PDGF alpha-receptor expression in the dorsoventral axis of the neural tube may define the origin of the oligodendrocyte lineage. Development 117(2), 525–533 (1993).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Sturrock, R. R. Myelination of the mouse corpus callosum. Neuropathol. Appl. Neurobiol. 6(6), 415–420 (1980).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Snaidero, N. & Simons, M. Myelination at a glance. J. Cell Sci. 127(Pt 14), 2999–3004 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Simons, M. & Trajkovic, K. Neuron-glia communication in the control of oligodendrocyte function and myelin biogenesis. J. Cell Sci. 119(Pt 21), 4381–4389 (2006).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Stassart, R. M. et al. The axon-myelin unit in development and degenerative disease. Front. Neurosci. 12, 467 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caldwell, J. H. et al. Sodium channel Na(v)1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc. Natl. Acad. Sci. U S A 97(10), 5616–20 (2000).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Einheber, S. et al. The axonal membrane protein Caspr, a homologue of neurexin IV, is a component of the septate-like paranodal junctions that assemble during myelination. J. Cell Biol. 139(6), 1495–1506 (1997).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Xin, W. & Chan, J. R. Myelin plasticity: Sculpting circuits in learning and memory. Nat. Rev. Neurosci. 21(12), 682–694 (2020).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Zdaniuk, G. et al. Astroglia disturbances during development of the central nervous system in fetuses with Down’s syndrome. Folia Neuropathol. 49(2), 109–114 (2011).

    PubMed 

    Google Scholar
     

  • Duchon, A. et al. Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: Relevance for modeling Down syndrome. Mamm. Genome 22(11–12), 674–684 (2011).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Perez-Catalan, N. A., Doe, C. Q. & Ackerman, S. D. The role of astrocyte-mediated plasticity in neural circuit development and function. Neural Dev. 16(1), 1 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Baldwin, K. T. & Eroglu, C. Molecular mechanisms of astrocyte-induced synaptogenesis. Curr. Opin. Neurobiol. 45, 113–120 (2017).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Brault, V. et al. Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome. PLoS Genet. 17(9), e1009777 (2021).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Grau, C. et al. DYRK1A-mediated phosphorylation of GluN2A at Ser(1048) regulates the surface expression and channel activity of GluN1/GluN2A receptors. Front. Cell Neurosci. 8, 331 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Araque, A. & Perea, G. Glial modulation of synaptic transmission in culture. Glia 47(3), 241–248 (2004).

    Article 
    PubMed 

    Google Scholar
     

  • Dallerac, G., Zapata, J. & Rouach, N. Versatile control of synaptic circuits by astrocytes: where, when and how?. Nat. Rev. Neurosci. 19(12), 729–743 (2018).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Marti, E. et al. Dyrk1A expression pattern supports specific roles of this kinase in the adult central nervous system. Brain Res. 964(2), 250–263 (2003).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Blanco-Suarez, E., Caldwell, A. L. & Allen, N. J. Role of astrocyte-synapse interactions in CNS disorders. J. Physiol. 595(6), 1903–1916 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • De Leon, R. N. S., Bragg-Gonzalo, L. & Nieto, M. Development and plasticity of the corpus callosum. Development 147(18), 555 (2020).


    Google Scholar
     

  • Just, M. A. et al. Functional and anatomical cortical underconnectivity in autism: Evidence from an FMRI study of an executive function task and corpus callosum morphometry. Cereb Cortex 17(4), 951–961 (2007).

    Article 
    PubMed 

    Google Scholar
     

  • Fenlon, L. R. & Richards, L. J. Contralateral targeting of the corpus callosum in normal and pathological brain function. Trends Neurosci. 38(5), 264–272 (2015).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Harting, I. et al. Abnormal myelination in Angelman syndrome. Eur. J. Paediatr. Neurol. 13(3), 271–276 (2009).

    Article 
    PubMed 

    Google Scholar
     

  • Kortum, F. et al. The core FOXG1 syndrome phenotype consists of postnatal microcephaly, severe mental retardation, absent language, dyskinesia, and corpus callosum hypogenesis. J. Med. Genet. 48(6), 396–406 (2011).

    Article 
    PubMed 

    Google Scholar
     

  • Zhao, C. et al. Dual requirement of CHD8 for chromatin landscape establishment and histone methyltransferase recruitment to promote CNS myelination and repair. Dev. Cell 45(6), 753-768 e8 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kawamura, A. et al. Oligodendrocyte dysfunction due to Chd8 mutation gives rise to behavioral deficits in mice. Hum. Mol. Genet. 29(8), 1274–1291 (2020).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Durand, B. & Raff, M. A cell-intrinsic timer that operates during oligodendrocyte development. BioEssays 22(1), 64–71 (2000).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Tomassy, G. S., Dershowitz, L. B. & Arlotta, P. Diversity matters: A revised guide to myelination. Trends Cell Biol. 26(2), 135–147 (2016).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Cleveland, D. W. Neuronal growth and death: Order and disorder in the axoplasm. Cell 84(5), 663–666 (1996).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kevenaar, J. T. & Hoogenraad, C. C. The axonal cytoskeleton: From organization to function. Front. Mol. Neurosci. 8, 44 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kirkcaldie, M. T. K. & Dwyer, S. T. The third wave: Intermediate filaments in the maturing nervous system. Mol. Cell Neurosci. 84, 68–76 (2017).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Nelson, A. D. & Jenkins, P. M. Axonal membranes and their domains: Assembly and function of the axon initial segment and node of Ranvier. Front. Cell Neurosci. 11, 136 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rasband, M. N. & Peles, E. Mechanisms of node of Ranvier assembly. Nat. Rev. Neurosci. 22, 7–20 (2020).

    Article 
    PubMed 

    Google Scholar
     

  • Souchet, B. et al. Excitation/inhibition balance and learning are modified by Dyrk1a gene dosage. Neurobiol. Dis. 69, 65–75 (2014).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Olmos-Serrano, J. L. et al. Down syndrome developmental brain transcriptome reveals defective oligodendrocyte differentiation and myelination. Neuron 89(6), 1208–1222 (2016).

    Article 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Barak, B. et al. Neuronal deletion of Gtf2i, associated with Williams syndrome, causes behavioral and myelin alterations rescuable by a remyelinating drug. Nat. Neurosci. 22(5), 700–708 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Kato, D. & Wake, H. Myelin plasticity modulates neural circuitry required for learning and behavior. Neurosci. Res. 167, 11–16 (2021).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Inoue, K. Pelizaeus-merzbacher disease: Molecular and cellular pathologies and associated phenotypes. Adv. Exp. Med. Biol. 1190, 201–216 (2019).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • Miller, D. J. et al. Prolonged myelination in human neocortical evolution. Proc. Natl. Acad. Sci. U S A 109(41), 16480–16485 (2012).

    Article 
    ADS 
    PubMed 
    PubMed Central 
    CAS 

    Google Scholar
     

  • Paxinos, G. & Franklin, K. B. J. The Mouse Brain in Stereotaxic Coordinates 2nd edn. (Elsevier, 2008).


    Google Scholar
     

  • Fernandez, E., Cuenca, N. & De Juan, J. A useful programme in BASIC for axonal morphometry with introduction of new cytoskeletal parameters. J. Neurosci. Methods. 39(3), 271–289 (1991).

    Article 
    PubMed 
    CAS 

    Google Scholar
     

  • https://www.nature.com/articles/s41598-022-24284-5