Overlapping and Non-overlapping Functions of Condensins I and II in Neural Stem Cell Divisions

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.

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…For example, after depletion of the core condensin subunit Smc2, mouse neural stem cells (NSCs) progressed through mitosis, underwent defective chromosome segregation and DNA damage-induced apoptosis. However, the depletion of Smc2 in human RPE-1 cells causes senescent-like phenotype and cell cycle arrest in G1 phase (Nishide and Hirano, 2014). Additionally, Smc5 knockdown in chicken DT40 lymphoma cells and human RPE-1 cells does not affect cell viability, although cells showed lower proliferation rates (Stephan et al, 2011;Gallego-Paez et al, 2014).…”

Conditional mutation of Smc5 in mouse embryonic stem cells perturbs condensin localization and mitotic progression

“…Condensins are crucial for early embryonic development and cerebral cortex formation in mice (Nishide and Hirano, 2014). Misregulation of condensin II has been implicated in the neurodevelopmental disorder autosomal recessive primary microcephaly (MCPH) (Hirano, 2012;Trimborn et al, 2006).…”

Condensin II mutation causes T-cell lymphoma through tissue-specific genome instability

“…Within cohesin and condensin complexes, the C and N termini of kleisin interact with apposing SMC subunits to form a tripartite, asymmetric ring-like structure that can entrap DNA (Gruber et al 2003;Onn et al 2007;Nasmyth and Oliveira 2010;Cuylen et al 2011; Piazza et al Cold Spring Harbor Laboratory Press on May 10, 2018 -Published by genesdev.cshlp.org Downloaded from 2014). This mode of association has been proposed to allow SMC complexes to form topological linkages between chromosomes or different regions on the same DNA molecule.Metazoan genomes encode at least two distinct condensin complexes (Ono et al 2003), which play nonredundant and incompletely understood roles in the regulation of chromosome architecture (Ono et al 2003;Green et al 2012;Hirano 2012;Nishide and Hirano 2014;Houlard et al 2015). Condensin I gains access to chromosomes between prometaphase and telophase, whereas condensin II is present in both the nucleus and cytoplasm during interphase and becomes concentrated on chromosome axes and centromeres during prophase (Hirota et al 2004;Ono et al 2004).…”

“…Evidence supporting this hypothesis recently arose from a gene network-based analysis of The Cancer Genome Atlas (TCGA) data set (Leiserson et al 2015). With the exception of SMC4, mutations in condensin subunits were not statistically enriched in tumor genomes when considered individually; however, statistical significance was reached when subunits were considered together as a Previous mouse models of condensin deficiency have focused primarily on loss-of-function mutations (Smith et al 2004;Nishide and Hirano 2014;Houlard et al 2015), which cause chromosome segregation failure followed by cellular and organismal lethality. However, the majority of condensin mutations in TCGA are missense and are likely to exert sublethal effects on chromosome structure.…”

“…Metazoan genomes encode at least two distinct condensin complexes (Ono et al 2003), which play nonredundant and incompletely understood roles in the regulation of chromosome architecture (Ono et al 2003;Green et al 2012;Hirano 2012;Nishide and Hirano 2014;Houlard et al 2015). Condensin I gains access to chromosomes between prometaphase and telophase, whereas condensin II is present in both the nucleus and cytoplasm during interphase and becomes concentrated on chromosome axes and centromeres during prophase (Hirota et al 2004;Ono et al 2004).…”