Mammalian Neurogenesis Requires Treacle-Plk1 for Precise Control of Spindle Orientation, Mitotic Progression, and Maintenance of Neural Progenitor Cells

Daisuke Sakai,Michael J Dixon,Paul A Trainor,Jill Dixon,Joseph S Takahashi

doi:10.1371/journal.pgen.1002566

Abstract

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.

Highlights

The cerebral cortex constitutes the outermost layer of the mammalian brain and is comprised of six morphologically and functionally distinct neuronal layers which provide humans with unique cognitive abilities, sensory perception and awareness
Tcof1 is essential for normal brain development Treacher Collins syndrome (TCS; OMIM#154500) is a congenital disorder of craniofacial development characterized by hypoplasia of the facial bones, the zygomatic complex and mandible together with cleft palate and anomalies in external and middle ear development [14]
TCS is caused by mutations in the TCOF1 gene, which encodes a nucleolar phosphoprotein known as Treacle [15] a role for TCOF1/Treacle in cortical neurogenesis and the regulation of brain size and pathogenesis of microcephaly has not been previously examined

Summary

Introduction

The cerebral cortex constitutes the outermost layer of the mammalian brain and is comprised of six morphologically and functionally distinct neuronal layers which provide humans with unique cognitive abilities, sensory perception and awareness. Later during the peak period of neurogenesis, neural progenitor cells increasingly undergo asymmetric cell division to self renew (apical progenitors) while simultaneously giving rise to a neuron or intermediate progenitor cell (basal progenitors) which can further divide symmetrically to produce neurons [2,3,4,5]. These postmitotic neurons differentiate and migrate away from the VZ to their final destinations in the cerebral cortex [6]. The overall structure or architecture of the brain may or may not be affected, but in each case microcephaly is strongly associated with mental retardation [9]

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