Abstract
During development of the cerebral cortex, neural stem cells (NSCs) divide symmetrically to proliferate and asymmetrically to generate neurons. Although faithful segregation of mitotic chromosomes is critical for NSC divisions, its fundamental mechanism remains unclear. A class of evolutionarily conserved protein complexes, known as condensins, is thought to be central to chromosome assembly and segregation among eukaryotes. Here we report the first comprehensive genetic study of mammalian condensins, demonstrating that two different types of condensin complexes (condensins I and II) are both essential for NSC divisions and survival in mice. Simultaneous depletion of both condensins leads to severe defects in chromosome assembly and segregation, which in turn cause DNA damage and trigger p53-induced apoptosis. Individual depletions of condensins I and II lead to slower loss of NSCs compared to simultaneous depletion, but they display distinct mitotic defects: chromosome missegregation was observed more prominently in NSCs depleted of condensin II, whereas mitotic delays were detectable only in condensin I-depleted NSCs. Remarkably, NSCs depleted of condensin II display hyperclustering of pericentric heterochromatin and nucleoli, indicating that condensin II, but not condensin I, plays a critical role in establishing interphase nuclear architecture. Intriguingly, these defects are taken over to postmitotic neurons. Our results demonstrate that condensins I and II have overlapping and non-overlapping functions in NSCs, and also provide evolutionary insight into intricate balancing acts of the two condensin complexes.
Highlights
The formation of the cerebral cortex requires a stringent control of cell proliferation and differentiation [1,2]
We study the functions of evolutionarily conserved chromosome regulators, known as condensin I and condensin II, during development of the cerebral cortex in mice
Our results demonstrate convincingly that an intricate balance between condensins I and II plays a crucial role in neural stem cells (NSCs) divisions
Summary
The formation of the cerebral cortex requires a stringent control of cell proliferation and differentiation [1,2]. At the early stages of cortical development, NSCs in the ventricular zone (VZ) adjacent to the lateral ventricle (LV) divide symmetrically to generate two daughter NSCs for expanding the cell population (Fig. 1A). NSCs undergo asymmetric divisions to give rise to pairs of a neuron and an NSC. NSCs generate lineage-committed intermediate progenitor cells that contribute to further amplification of the number of neurons. Born neurons migrate away from the VZ into the cortical plate (CP) in a birthdate-dependent manner. Both proliferation and differentiation of NSCs rely on a series of symmetrical and asymmetrical cell divisions, where two daughter cells must receive a complete set of chromosomes. The basic mechanism of chromosome inheritance is often overlooked in the studies of NSCs with a few exceptions [3]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
