Spindle orientation: What if it goes wrong?

Bergstralh, Daniel T.; Johnston, Daniel St

doi:10.1016/j.semcdb.2014.06.014

Cited by 35 publications

(32 citation statements)

References 72 publications

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“…The orientation of cell division is carefully controlled in both embryonic and adult tissues, in which it may regulate cell fate, generate tissue shape, and maintain normal histological architecture [1][2][3]. Studies conducted over the last two decades have established that this process may play an important role to regulate the delicate balance between proliferation and differentiation that underlies normal brain development, with particular regard to the generation of a normal number of cortical neurons [2,4,5].…”

Section: Introductionmentioning

confidence: 99%

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

et al. 2016

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Correct orientation of cell division is considered an important factor for the achievement of normal brain size, as mutations in genes that affect this process are among the leading causes of microcephaly. Abnormal spindle orientation is associated with reduction of the neuronal progenitor symmetric divisions, premature cell cycle exit, and reduced neurogenesis. This mechanism has been involved in microcephaly resulting from mutation of ASPM, the most frequently affected gene in autosomal recessive human primary microcephaly (MCPH), but it is presently unknown how ASPM regulates spindle orientation. In this report, we show that ASPM may control spindle positioning by interacting with citron kinase (CITK), a protein whose loss is also responsible for severe microcephaly in mammals. We show that the absence of CITK leads to abnormal spindle orientation in mammals and insects. In mouse cortical development, this phenotype correlates with increased production of basal progenitors. ASPM is required to recruit CITK at the spindle, and CITK overexpression rescues ASPM phenotype. ASPM and CITK affect the organization of astral microtubules (MT), and low doses of MT-stabilizing drug revert the spindle orientation phenotype produced by their knockdown. Finally, CITK regulates both astral-MT nucleation and stability. Our results provide a functional link between two established microcephaly proteins.

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Section: Introductionmentioning

confidence: 99%

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

et al. 2016

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“…Another possibility is that some tissues are more sensitive than others to the loss of CIT-K. For instance, Sgrò et al proposed recently that the expression of the tissue-specific tubulin variant TUBB3 sensitizes cultured neuronal progenitors to CIT-K loss (Sgrò et al, 2016); however, we could not find a correlation between TUBB3 expression and CIT-K depletion in various cancer cell lines ( . It is also important to point out that CIT-K is involved in both spindle orientation and midbody formation, two events that have been implicated in establishing cell fate and polarity ( Bergstralh and St Johnston, 2014;Dionne et al, 2015). Therefore, it would be interesting to know whether CIT-K functions in yet more biological processes, such as stemness, differentiation, and tissue organization and remodelling.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

Citron kinase – renaissance of a neglected mitotic kinase

D’Avino

2017

Journal of Cell Science

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Cell division controls the faithful segregation of genomic and cytoplasmic materials between the two nascent daughter cells. Members of the Aurora, Polo and cyclin-dependent (Cdk) kinase families are known to regulate multiple events throughout cell division, whereas another kinase, citron kinase (CIT-K), for a long time has been considered to function solely during cytokinesis, the last phase of cell division. CIT-K was originally proposed to regulate the ingression of the cleavage furrow that forms at the equatorial cortex of the dividing cell after chromosome segregation. However, studies in the last decade have clarified that this kinase is, instead, required for the organization of the midbody in late cytokinesis, and also revealed novel functions of CIT-K earlier in mitosis and in DNA damage control. Moreover, CIT-K mutations have recently been linked to the development of human microcephaly, and CIT-K has been identified as a potential target in cancer therapy. In this Commentary, I describe and re-evaluate the functions and regulation of CIT-K during cell division and its involvement in human disease. Finally, I offer my perspectives on the open questions and future challenges that are necessary to address, in order to fully understand this important and yet unjustly neglected mitotic kinase.

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“…The G protein Gαi accumulates at designated anchoring sites and mobilizes LGN, a large scaffold protein. LGN in turn is responsible for recruitment of the microtubule binding protein NuMA and the motor complex dynein/dynactin, which provides plus end directed microtubule-pulling forces (Figure 4) [85, 88]. Core components of the spindle pole anchoring machinery are also present in cells, where they may play a central role in spindle orientation and anchoring as well [88, 89].…”

Section: Abnormal Centrosome Dynamicsmentioning

confidence: 99%

“…LGN in turn is responsible for recruitment of the microtubule binding protein NuMA and the motor complex dynein/dynactin, which provides plus end directed microtubule-pulling forces (Figure 4) [85, 88]. Core components of the spindle pole anchoring machinery are also present in cells, where they may play a central role in spindle orientation and anchoring as well [88, 89]. It will therefore be interesting to explore whether these components are subject to deregulation in cells with spindle geometry defects due to abnormal spindle pole anchoring.…”

Section: Abnormal Centrosome Dynamicsmentioning

confidence: 99%

Centrosome dynamics as a source of chromosomal instability

Nam

Naylor

Deursen

2015

Trends in Cell Biology

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Accurate segregation of duplicated chromosomes between two daughter cells depends on bi-polar spindle formation, a metaphase state in which sister kinetochores are attached to microtubules emanating from opposite spindle poles. To ensure bi-orientation, cells possess surveillance systems that safeguard against microtubule-kinetochore attachment defects, including the spindle assembly checkpoint and the error correction machinery. However, recent developments have identified centrosome dynamics – that is, centrosome disjunction and poleward movement of duplicated centrosomes – as a central target for deregulation of bi-orientation in cancer cells. Here we review novel insights into the mechanisms that underlie centrosome dynamics and discuss how these mechanisms are perturbed in cancer cells to drive chromosome missegregation and advance neoplastic transformation.

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Spindle orientation: What if it goes wrong?

Abstract: HighlightsSpindle orientation is important to both cell fate and tissue architecture.Multiple mechanisms act to limit the consequences of metaphase spindle misorientation.One such mechanism may involve the anaphase function of NuMA/Mud/Lin-5.

Cited by 35 publications

References 72 publications

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

ASPM and CITK regulate spindle orientation by affecting the dynamics of astral microtubules

Citron kinase – renaissance of a neglected mitotic kinase

Centrosome dynamics as a source of chromosomal instability

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