Analysis and modeling of mitotic spindle orientations in three dimensions

Jüschke, Christoph; Xie, Yunyun; Postiglione, Maria Pia; Knoblich, Juergen A.

doi:10.1073/pnas.1314984111

Cited by 35 publications

(45 citation statements)

References 33 publications

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“…Our 3D en face analysis (Juschke et al, 2014) excludes mitotic spindle orientation as a major mechanism in Wdr62 and Aspm mutant mice, as we detected no difference in neural progenitor spindle orientation between WT, Wdr62 +/−; Aspm −/− and Wdr62 −/− embryos, suggesting that other mechanisms contribute to the microcephaly observed in these mutants. Our finding that Aspm and Wdr62 function together to promote centriole duplication provides a novel insight into how defects in centriole biogenesis may underlie the pathogenesis of MCPH.…”

Section: Discussionmentioning

confidence: 72%

“…Wdr62 −/− and Wdr62 −/−; Aspm +/− mice analyzed at E12.5 for mitotic spindle orientation using conventional 2D microscopy as well as a 3D en face technique in flat-mount cortex (Juschke et al, 2014) did not show consistent changes in mutants. We found that spindle orientation in the mutants was not significantly different from controls in anaphase (Figure 2H), indicating that spindle orientation changes are unlikely to explain the microcephaly in these mutants.…”

Section: Resultsmentioning

confidence: 92%

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Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Jayaraman

Kodani

Gonzalez

et al. 2016

Neuron

126

202

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SUMMARY Mutations in several genes encoding centrosomal proteins dramatically decrease the size of the human brain. We show that Aspm and Wdr62 interact genetically to control brain size, with mice lacking Wdr62, Aspm or both showing gene dose-related centriole duplication defects that parallel the severity of the microcephaly, and increased ectopic basal progenitors, suggesting premature delamination from the ventricular zone. Wdr62 and Aspm localize to the proximal end of the mother centriole and interact physically, with Wdr62 required for Aspm localization, and both proteins, as well as microcephaly protein Cep63, required to localize CENPJ/CPAP/Sas-4, a final common target. Unexpectedly, Aspm and Wdr62 are required for normal apical complex localization and apical epithelial structure, providing a plausible unifying mechanism for the premature delamination and precocious differentiation of progenitors. Together, our results reveal links between centrioles, apical proteins, and cell fate, and illuminate how alterations in these interactions can dynamically regulate brain size.

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Section: Discussionmentioning

confidence: 72%

Section: Resultsmentioning

confidence: 92%

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Jayaraman

Kodani

Gonzalez

et al. 2016

Neuron

126

202

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“…As two-dimensional analysis of the spindle axis can lead to systematic measurement errors (Juschke et al 2014), metaphase and anaphase apical progenitors were imaged by spinningdisc confocal microscope, and axis orientation was determined in three dimensions. The angle between the line bisecting both spindle poles (mitotic centrosomal marker, Aurora A) and the plane of the ventricular surface was measured in E13.5 brain sections ( Fig.…”

Section: Chromatin Bridges In Ncaph2 Apical Neural Progenitors Lead Tmentioning

confidence: 99%

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

et al. 2016

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Compaction of chromosomes is essential for accurate segregation of the genome during mitosis. In vertebrates, two condensin complexes ensure timely chromosome condensation, sister chromatid disentanglement, and maintenance of mitotic chromosome structure. Here, we report that biallelic mutations in NCAPD2, NCAPH, or NCAPD3, encoding subunits of these complexes, cause microcephaly. In addition, hypomorphic Ncaph2 mice have significantly reduced brain size, with frequent anaphase chromatin bridge formation observed in apical neural progenitors during neurogenesis. Such DNA bridges also arise in condensin-deficient patient cells, where they are the consequence of failed sister chromatid disentanglement during chromosome compaction. This results in chromosome segregation errors, leading to micronucleus formation and increased aneuploidy in daughter cells. These findings establish "condensinopathies" as microcephalic disorders, with decatenation failure as an additional disease mechanism for microcephaly, implicating mitotic chromosome condensation as a key process ensuring mammalian cerebral cortex size.

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“…line, was used as the reference, as reported (Juschke et al, 2014). Further details can be found in the supplementary Materials and Methods.…”

Section: Mitotic Spindle Orientationmentioning

confidence: 99%

The LGN protein promotes planar proliferative divisions in the neocortex but apicobasal asymmetric terminal divisions in the retina

Lacomme

Tarchini

Boudreau-Pinsonneault

et al. 2016

Development

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Cell division orientation is crucial to control segregation of polarized fate determinants in the daughter cells to produce symmetric or asymmetric fate outcomes. Most studies in vertebrates have focused on the role of mitotic spindle orientation in proliferative asymmetric divisions and it remains unclear whether altering spindle orientation is required for the production of asymmetric fates in differentiative terminal divisions. Here, we show that the GoLoco motif protein LGN, which interacts with Gαi to control apicobasal division orientation in Drosophila neuroblasts, is excluded from the apical domain of retinal progenitors undergoing planar divisions, but not in those undergoing apicobasal divisions. Inactivation of LGN reduces the number of apicobasal divisions in mouse retinal progenitors, whereas it conversely increases these divisions in cortical progenitors. Although LGN inactivation increases the number of progenitors outside the ventricular zone in the developing neocortex, it has no effect on the position or number of progenitors in the retina. Retinal progenitor cell lineage analysis in LGN mutant mice, however, shows an increase in symmetric terminal divisions producing two photoreceptors, at the expense of asymmetric terminal divisions producing a photoreceptor and a bipolar or amacrine cell. Similarly, inactivating Gαi decreases asymmetric terminal divisions, suggesting that LGN function with Gαi to control division orientation in retinal progenitors. Together, these results show a context-dependent function for LGN and indicate that apicobasal divisions are not involved in proliferative asymmetric divisions in the mouse retina, but are instead essential to generate binary fates at terminal divisions.

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Analysis and modeling of mitotic spindle orientations in three dimensions

Cited by 35 publications

References 33 publications

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Microcephaly Proteins Wdr62 and Aspm Define a Mother Centriole Complex Regulating Centriole Biogenesis, Apical Complex, and Cell Fate

Mutations in genes encoding condensin complex proteins cause microcephaly through decatenation failure at mitosis

The LGN protein promotes planar proliferative divisions in the neocortex but apicobasal asymmetric terminal divisions in the retina

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