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Title: Overlapping and Non-overlapping Functions of Condensins I and II in Neural Stem Cell Divisions}
Article:
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.
Introduction:
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 then undergo asymmetric divisions to give rise to pairs of a neuron and an NSC. NSCs also generate lineage-committed intermediate progenitor cells that contribute to further amplification of the number of neurons. Newly born neurons migrate away from the VZ into the cortical plate( CP) in a birthdate-dependent manner. Thus, 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. Despite its importance, however, the basic mechanism of chromosome inheritance is often overlooked in the studies of NSCs with a few exceptions[3]. Faithful assembly and segregation of chromosomes during mitosis rely on a class of multisubunit protein complexes, known as condensins[4]. Many eukaryotic organisms have two different condensin complexes( condensin I and condensin II) although a limited number of organisms including fungi have condensin I only. It remains unknown why the two condensin complexes are widespread among eukaryotes. Surprisingly, it has been shown that condensin II is not essential for mitosis in several model organisms[5],[6], and that condensin II has specialized non-mitotic functions, such as polytene chromosome disassembly in Drosophila melanogaster[7] and stress response in Arabidopsis thaliana[8]. In Xenopus egg extracts, condensin II has only a minor contribution to mitotic chromosome architecture[9]. Moreover, MCPH1, whose dysfunctions cause primary microcephaly in humans[10], has been shown to function as a potent inhibitor of condensin II[11], implicating that the action of condensin II may strongly be suppressed during cortical development. All these data suggest that condensin I is the major player in mitotic chromosome assembly and segregation among eukaryotes. A notable exception to this view exists, however: condensin II plays a dominant role over condensin I during early embryonic divisions in Caenorhabditis elegans[12]. This unique feature could be due to the occurrence of the holocentric chromosome structure in this particular organism. In vertebrates, experiments involving functional knockdown of condensin subunits have been limited to those using tissue culture cells[13]–[15], and no systematic genetic studies at an organismic level have been reported so far. Equally important, it has been difficult to follow the physiological fate of condensin-depleted cells in studies using tissue culture cells. In the current study, we have generated several strains of conditional knockout( cKO) mice to investigate the roles of condensins I and II in NSC divisions during cortical development. Contrary to the prediction described above, we find that condensins I and II are both essential to ensure NSC divisions and survival: loss of either one of condensins induces DNA damage and p53 nuclear accumulation, eventually leading to apoptosis. Simultaneous depletion of both condensins causes a severer set of defective phenotypes, indicating that the two complexes have overlapping functions. Remarkably, however, depletion of individual condensin causes distinct phenotypes, indicating that they have non-overlapping functions, too. Most notably, it is found that pericentromeric heterochromatin regions form abnormally large clusters in condensin II-depleted NSCs and postmitotic neurons. Our results clearly delineate the essential and distinct functions of the two condensin complexes in NSC divisions during cortical development.
Discussion:
The current study represents the first comprehensive genetic study of condensins in mammals. Unlike many other model organisms, our results show that condensins I and II are both essential for early embryonic development as well as cortical development in mice( Fig. 7A). As judged by the anatomical and marker expression analyses, condensins I and II have almost equal contributions to NSC division and subsequent cell survival. Simultaneous depletion of both condensins causes much severer defects than individual depletions, indicating that the two complexes share overlapping functions. Consistent with the anatomical analyses, Smc2 cKO mice displayed severe defects in chromosome assembly and segregation( Fig. 7B). Furthermore, the unique cell-division patterns during cortical development have allowed us to follow the fate of cells depleted of condensins in the brain. Our results suggest that the severe segregation defect observed in Smc2 cKO mice causes DNA damage and p53-induced apoptosis, resulting in a failure to build the cerebral cortex. Although the defective phenotypes observed in Ncaph and Ncaph2 cKO mice were milder than those observed in Smc2 cKO or DcKO mice, there are notable phenotypic differences between Ncaph and Ncaph2 cKO mice, indicating that condensins I and II have non-overlapping functions, too( Fig. 7B). Chromosome missegregation was observed more prominently in NSCs depleted of condensin II, whereas mitotic delays were detectable only in condensin I-depleted NSCs. This observation raises the possibility that depletion of condensin I might confer an additional source of DNA damage. In fact, DNA damage induced by mitotic delay or arrest has been discussed in the literature although its underlying mechanism remains under debate[37]–[39]. Besides the mitotic defects which result in apoptosis in the VZ, the most dramatic differences between Ncaph and Ncaph2 cKO mice were observed in interphase nuclear architecture: hyperclustering of chromocenters and structural alternation of the nucleolus were uniquely observed in cells depleted of condensin II. Consistently, condensin II, but not condensin I, resides in the nucleus during interphase in NSCs. It is reasonable to speculate that condensin II separates non-homologous chromosomes from each other in NSCs by using the same mechanism that promotes the formation of chromosome territory in D. melanogaster polyploid cells[40] or resolves sister chromatids during S phase in human cells[41]. Our results also show that, once nuclear architecture is established by condensin II in NSCs, it seems to be taken over stably to postmitotic neurons. Interestingly, DNA damage and apoptosis were observed in a subpopulation of neurons in Ncaph2 cKO mice, the mechanism of which is currently unknown. In this sense, it is noteworthy that a hypomorphic mutation of Ncaph2 was reported to specifically affect T-cell differentiation and survival in mice[42], presumably through a failure in condensin II-dependent structural reorganization of interphase chromatin[43]. On the other hand, it has been shown that overexpression of methyl-CpG-binding protein 2( MeCP2), whose mutations cause the neurodevelopmental disorder Rett syndrome[44], induce hyperclustering of chromocenters in mouse cells[30],[31]. Moreover, loss of MeCP2 results in structural alternation of the nucleolus in cortical neurons[45], raising the possibility that MeCP2 somehow counteracts condensin II in neurons. Unlike condensin II that functions in NSCs, however, MeCP2 is expressed and functions in postmitotic neurons but not in NSCs[46]. It is therefore reasonable to speculate that condensin II regulates interphase nuclear architecture and neuronal survival independently of MeCP2. Interestingly, we notice that the relative contribution of the two condensin complexes to cell divisions as well as the downstream responses to condensin depletions is cell type-dependent. In human RPE-1 cells, for instance, depletion of condensin II causes DNA damage and p53 nuclear accumulation, which in turn induces cell cycle arrest through up-regulation of p21. Because DNA damage is far less prominent in condensin I-depleted RPE-1 cells, the proliferative ability of the two sets of cells was strikingly different from each other. Similar yet non-identical results have been reported from a previous study using chicken DT40 cell lines in which individual, specific subunits of condensins I and II were genetically depleted[15]. They showed that depletion of condensin II causes severe segregation defects whereas depletion of condensin I results in a failure in cytokinesis without delaying mitotic progression. On the other hand, a study using mouse embryonic stem( ES) cells reported that condensins I and II have only overlapping functions in cell survival[28]. These studies further support our idea that cellular responses to depletion of condensins are seemingly different among different cell types or cell lines. Taken together, we argue that comparative analyses of the two condensin complexes offer an excellent example of how deep understanding of the physiological complexity requires broad perspectives of cell, developmental and evolutionary biology. NSCs with oncogenic mutations acquire a high proliferative capacity with impaired differentiation potential, generating malignant brain tumors known as glioblastoma[47],[48]. The mechanistic basis behind tumorigenesis is not fully understood, however. It has recently been reported that SMC2 is overexpressed in colorectal cancer[49] or neuroblastoma[50] cells. Given our results discussed above, it is possible that intricate balancing acts of condensins I and II, rather than simple upregulation or downregulation of their components, are altered in different types of cancer cells. We anticipate that further extension of the current study will help understand the fundamental differences between stem cells and cancer cells, if any, from a point of view of chromosome architecture and dynamics.
The cerebral cortex is built up of numerous neurons and cells supporting them , most of which originate from neural stem cells ( NSCs ) . NSCs divide symmetrically to produce themselves and asymmetrically to generate neurons , and both types of divisions reply on faithful segregation of chromosomes into daughter cells . In the current study , we study the functions of evolutionarily conserved chromosome regulators , known as condensin I and condensin II , during development of the cerebral cortex in mice . We find that condensins I and II have both overlapping and non-overlapping functions in NSC divisions and survival: loss of either one of condensins causes distinct abnormalities in the process of chromosome segregation . Remarkably , loss of condensin II , but not of condensin I , also alters chromosome architecture during non-dividing stages . Our results demonstrate convincingly that an intricate balance between condensins I and II plays a crucial role in NSC divisions . It will be of great interest to test in the future whether such balancing acts of the two condensin complexes might be misregulated in tumorigenic NSCs that undergo uncontrolled cell divisions .