Tubb3 expression levels are sensitive to neuronal activity changes and determine microtubule growth and kinesin-mediated transport
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Tubb3 expression levels are sensitive to neuronal activity changes and determine microtubule growth and kinesin-mediated transport. / Radwitz, Jennifer; Hausrat, Torben J; Heisler, Frank F; Janiesch, Philipp C; Pechmann, Yvonne; Rübhausen, Michael; Kneussel, Matthias.
In: CELL MOL LIFE SCI, Vol. 79, No. 11, 575, 29.10.2022.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - Tubb3 expression levels are sensitive to neuronal activity changes and determine microtubule growth and kinesin-mediated transport
AU - Radwitz, Jennifer
AU - Hausrat, Torben J
AU - Heisler, Frank F
AU - Janiesch, Philipp C
AU - Pechmann, Yvonne
AU - Rübhausen, Michael
AU - Kneussel, Matthias
N1 - © 2022. The Author(s).
PY - 2022/10/29
Y1 - 2022/10/29
N2 - Microtubules are dynamic polymers of α/β-tubulin. They regulate cell structure, cell division, cell migration, and intracellular transport. However, functional contributions of individual tubulin isotypes are incompletely understood. The neuron-specific β-tubulin Tubb3 displays highest expression around early postnatal periods characterized by exuberant synaptogenesis. Although Tubb3 mutations are associated with neuronal disease, including abnormal inhibitory transmission and seizure activity in patients, molecular consequences of altered Tubb3 levels are largely unknown. Likewise, it is unclear whether neuronal activity triggers Tubb3 expression changes in neurons. In this study, we initially asked whether chemical protocols to induce long-term potentiation (cLTP) affect microtubule growth and the expression of individual tubulin isotypes. We found that growing microtubules and Tubb3 expression are sensitive to changes in neuronal activity and asked for consequences of Tubb3 downregulation in neurons. Our data revealed that reduced Tubb3 levels accelerated microtubule growth in axons and dendrites. Remarkably, Tubb3 knockdown induced a specific upregulation of Tubb4 gene expression, without changing other tubulin isotypes. We further found that Tubb3 downregulation reduces tubulin polyglutamylation, increases KIF5C motility and boosts the transport of its synaptic cargo N-Cadherin, which is known to regulate synaptogenesis and long-term potentiation. Due to the large number of tubulin isotypes, we developed and applied a computational model based on a Monte Carlo simulation to understand consequences of tubulin expression changes in silico. Together, our data suggest a feedback mechanism with neuronal activity regulating tubulin expression and consequently microtubule dynamics underlying the delivery of synaptic cargoes.
AB - Microtubules are dynamic polymers of α/β-tubulin. They regulate cell structure, cell division, cell migration, and intracellular transport. However, functional contributions of individual tubulin isotypes are incompletely understood. The neuron-specific β-tubulin Tubb3 displays highest expression around early postnatal periods characterized by exuberant synaptogenesis. Although Tubb3 mutations are associated with neuronal disease, including abnormal inhibitory transmission and seizure activity in patients, molecular consequences of altered Tubb3 levels are largely unknown. Likewise, it is unclear whether neuronal activity triggers Tubb3 expression changes in neurons. In this study, we initially asked whether chemical protocols to induce long-term potentiation (cLTP) affect microtubule growth and the expression of individual tubulin isotypes. We found that growing microtubules and Tubb3 expression are sensitive to changes in neuronal activity and asked for consequences of Tubb3 downregulation in neurons. Our data revealed that reduced Tubb3 levels accelerated microtubule growth in axons and dendrites. Remarkably, Tubb3 knockdown induced a specific upregulation of Tubb4 gene expression, without changing other tubulin isotypes. We further found that Tubb3 downregulation reduces tubulin polyglutamylation, increases KIF5C motility and boosts the transport of its synaptic cargo N-Cadherin, which is known to regulate synaptogenesis and long-term potentiation. Due to the large number of tubulin isotypes, we developed and applied a computational model based on a Monte Carlo simulation to understand consequences of tubulin expression changes in silico. Together, our data suggest a feedback mechanism with neuronal activity regulating tubulin expression and consequently microtubule dynamics underlying the delivery of synaptic cargoes.
KW - Humans
KW - Tubulin/genetics
KW - Kinesins/genetics
KW - Microtubules/metabolism
KW - Neurons/metabolism
KW - Axons/metabolism
U2 - 10.1007/s00018-022-04607-5
DO - 10.1007/s00018-022-04607-5
M3 - SCORING: Journal article
C2 - 36309617
VL - 79
JO - CELL MOL LIFE SCI
JF - CELL MOL LIFE SCI
SN - 1420-682X
IS - 11
M1 - 575
ER -