Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis.
Dendritic arborization patterns are consistent anatomical correlates of genetic disorders such as Down syndrome (DS) and autism spectrum disorders (ASDs). In a screen for abnormal dendrite development, we identified Minibrain (MNB)/DYRK1a, a kinase implicated in DS and ASDs, as a regulator of the microtubule cytoskeleton. We show that MNB is necessary to establish the length and cytoskeletal composition of terminal dendrites by controlling microtubule growth. Altering MNB levels disrupts dendrite morphology and perturbs neuronal electrophysiological activity, resulting in larval mechanosensation defects. Using in vivo and in vitro approaches, we uncover a molecular pathway whereby direct phosphorylation of β-tubulin by MNB inhibits tubulin polymerization, a function that is conserved for mammalian DYRK1a. Our results demonstrate that phosphoregulation of microtubule dynamics by MNB/DYRK1a is critical for dendritic patterning and neuronal function, revealing a previously unidentified mode of posttranslational microtubule regulation in neurons and uncovering a conserved pathway for a DS- and ASD-associated kinase.
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Kassandra M
KM
Ori-McKenney
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Richard J
RJ
McKenney
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
Hector H
HH
Huang
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Tun
T
Li
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Shan
S
Meltzer
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Lily Yeh
LY
Jan
Department of Cellular and Molecular Pharmacology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Ronald D
RD
Vale
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA 94158, USA.
Arun P
AP
Wiita
Department of Physiology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: yuhnung.jan@ucsf.edu.
Yuh Nung
YN
Jan
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster; D008870:Microtubules / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014404:Tubulin / Q000235:genetics / Q000378:metabolism*; D000097603:Dyrk Kinases
D029721:Drosophila Proteins; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D014404:Tubulin; C092066:mnb protein, Drosophila; D000097603:Dyrk Kinases