Mammalian neurogenesis requires Treacle-Plk1 for precise control of spindle orientation, mitotic progression, and maintenance of neural progenitor cells

The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric...

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Bibliographic Details
Published in:PLoS genetics 2012-03, Vol.8 (3), p.e1002566-e1002566
Main Authors: Sakai, Daisuke, Dixon, Jill, Dixon, Michael J, Trainor, Paul A
Format: Article
Language:English
Subjects:
Animals
Biology
Cell cycle
Cell Cycle Checkpoints - genetics
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell division
Cell Proliferation
Cellular biology
Centrosome - metabolism
Cerebral Cortex - abnormalities
Cerebral Cortex - growth & development
Gene Expression Regulation, Developmental
HeLa Cells
Humans
Intracellular Signaling Peptides and Proteins
M Phase Cell Cycle Checkpoints - genetics
Mandibulofacial Dysostosis - genetics
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Mutant Strains
Mitosis
Mitosis - genetics
Neurogenesis
Neurogenesis - genetics
Neurons
Neurons - cytology
Neurons - metabolism
Nuclear Proteins - genetics
Nuclear Proteins - metabolism
Phosphoproteins - genetics
Phosphoproteins - metabolism
Physiological aspects
Polo-Like Kinase 1
Protein Serine-Threonine Kinases - genetics
Protein Serine-Threonine Kinases - metabolism
Proteins
Proto-Oncogene Proteins - genetics
Proto-Oncogene Proteins - metabolism
Spindle (Cell division)
Stem cells
Stem Cells - cytology
Stem Cells - metabolism
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Summary:The cerebral cortex is a specialized region of the brain that processes cognitive, motor, somatosensory, auditory, and visual functions. Its characteristic architecture and size is dependent upon the number of neurons generated during embryogenesis and has been postulated to be governed by symmetric versus asymmetric cell divisions, which mediate the balance between progenitor cell maintenance and neuron differentiation, respectively. The mechanistic importance of spindle orientation remains controversial, hence there is considerable interest in understanding how neural progenitor cell mitosis is controlled during neurogenesis. We discovered that Treacle, which is encoded by the Tcof1 gene, is a novel centrosome- and kinetochore-associated protein that is critical for spindle fidelity and mitotic progression. Tcof1/Treacle loss-of-function disrupts spindle orientation and cell cycle progression, which perturbs the maintenance, proliferation, and localization of neural progenitors during cortical neurogenesis. Consistent with this, Tcof1(+/-) mice exhibit reduced brain size as a consequence of defects in neural progenitor maintenance. We determined that Treacle elicits its effect via a direct interaction with Polo-like kinase1 (Plk1), and furthermore we discovered novel in vivo roles for Plk1 in governing mitotic progression and spindle orientation in the developing mammalian cortex. Increased asymmetric cell division, however, did not promote increased neuronal differentiation. Collectively our research has therefore identified Treacle and Plk1 as novel in vivo regulators of spindle fidelity, mitotic progression, and proliferation in the maintenance and localization of neural progenitor cells. Together, Treacle and Plk1 are critically required for proper cortical neurogenesis, which has important implications in the regulation of mammalian brain size and the pathogenesis of congenital neurodevelopmental disorders such as microcephaly.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/journal.pgen.1002566