Abstract
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. Ori-McKenney et al. identify a conserved mechanism for a Down syndrome critical kinase in regulating microtubule growth during neuronal development. MNB/DYRK1a inhibits microtubule polymerization by phosphorylating tubulin, a pathway that contributes to proper dendritic patterning and overall neuronal function.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 551-563 |
| Number of pages | 13 |
| Journal | Neuron |
| Volume | 90 |
| Issue number | 3 |
| DOIs | |
| State | Published - May 4 2016 |
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ASJC Scopus subject areas
- Neuroscience(all)
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Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis. / Ori-McKenney, Kassandra M.; Mckenney, Richard; Huang, Hector H.; Li, Tun; Meltzer, Shan; Jan, Lily Yeh; Vale, Ronald D.; Wiita, Arun P.; Jan, Yuh Nung.
In: Neuron, Vol. 90, No. 3, 04.05.2016, p. 551-563.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Phosphorylation of β-Tubulin by the Down Syndrome Kinase, Minibrain/DYRK1a, Regulates Microtubule Dynamics and Dendrite Morphogenesis
AU - Ori-McKenney, Kassandra M.
AU - Mckenney, Richard
AU - Huang, Hector H.
AU - Li, Tun
AU - Meltzer, Shan
AU - Jan, Lily Yeh
AU - Vale, Ronald D.
AU - Wiita, Arun P.
AU - Jan, Yuh Nung
PY - 2016/5/4
Y1 - 2016/5/4
N2 - 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. Ori-McKenney et al. identify a conserved mechanism for a Down syndrome critical kinase in regulating microtubule growth during neuronal development. MNB/DYRK1a inhibits microtubule polymerization by phosphorylating tubulin, a pathway that contributes to proper dendritic patterning and overall neuronal function.
AB - 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. Ori-McKenney et al. identify a conserved mechanism for a Down syndrome critical kinase in regulating microtubule growth during neuronal development. MNB/DYRK1a inhibits microtubule polymerization by phosphorylating tubulin, a pathway that contributes to proper dendritic patterning and overall neuronal function.
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UR - http://www.scopus.com/inward/citedby.url?scp=84963954562&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2016.03.027
DO - 10.1016/j.neuron.2016.03.027
M3 - Article
C2 - 27112495
AN - SCOPUS:84963954562
VL - 90
SP - 551
EP - 563
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 3
ER -