TUBB5 and its disease-associated mutations influence the terminal differentiation and dendritic spine densities of cerebral cortical neurons.
The microtubule cytoskeleton is critical for the generation and maturation of neurons in the developing mammalian nervous system. We have previously shown that mutations in the β-tubulin gene TUBB5 cause microcephaly with structural brain abnormalities in humans. While it is known that TUBB5 is necessary for the proper generation and migration of neurons, little is understood of the role it plays in neuronal differentiation and connectivity. Here, we report that perturbations to TUBB5 disrupt the morphology of cortical neurons, their neuronal complexity, axonal outgrowth, as well as the density and shape of dendritic spines in the postnatal murine cortex. The features we describe are consistent with defects in synaptic signaling. Cellular-based assays have revealed that TUBB5 substitutions have the capacity to alter the dynamic properties and polymerization rates of the microtubule cytoskeleton. Together, our studies show that TUBB5 is essential for neuronal differentiation and dendritic spine formation in vivo, providing insight into the underlying cellular pathology associated with TUBB5 disease states.
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Linh
L
Ngo
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Matilda
M
Haas
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Zhengdong
Z
Qu
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Shan Shan
SS
Li
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia.
Jennifer
J
Zenker
The Anatomy and Neuroscience Department, University of Melbourne, Parkville, VIC 3010, Australia.
Kathleen Sue Lyn
KS
Teng
The Anatomy and Neuroscience Department, University of Melbourne, Parkville, VIC 3010, Australia The Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010, Australia.
Jenny Margaret
JM
Gunnersen
Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria.
Martin
M
Breuss
The Anatomy and Neuroscience Department, University of Melbourne, Parkville, VIC 3010, Australia.
Mark
M
Habgood
Institute of Molecular Pathology, Dr Bohr-Gasse, Vienna 1030, Austria, julian.heng@monash.edu david.keays@imp.ac.at.
David Anthony
DA
Keays
EMBL Australia, The Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia, julian.heng@monash.edu david.keays@imp.ac.at.
Julian Ik-Tsen
JI
Heng
D000818:Animals; D001369:Axons / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism*; D049229:Dendritic Spines / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D017930:Genes, Reporter; D051379:Mice; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D009154:Mutation; D009474:Neurons / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D055503:Protein Multimerization; D034622:RNA Interference; D014404:Tubulin / Q000235:genetics*
C000598026:TUBB5 protein, mouse; D014404:Tubulin