Understanding microcephaly through the study of centrosome regulation in Drosophila neural stem cells

Microcephaly is a rare, yet devastating, neurodevelopmental condition caused by genetic or environmental insults, such as the Zika virus infection. Microcephaly manifests with a severely reduced head circumference. Among the known heritable microcephaly genes, a significant proportion are annotated with centrosome-related ontologies. Centrosomes are microtubule-organizing centers, and they play fundamental roles in the proliferation of the neuronal progenitors, the neural stem cells (NSCs), which undergo repeated rounds of asymmetric cell division to drive neurogenesis and brain development. Many of the genes, pathways, and developmental paradigms that dictate NSC development in humans are conserved in Drosophila melanogaster. As such, studies of Drosophila NSCs lend invaluable insights into centrosome function within NSCs and help inform the pathophysiology of human microcephaly. This mini-review will briefly survey causative links between deregulated centrosome functions and microcephaly with particular emphasis on insights learned from Drosophila NSCs.

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PLP inhibits the activity of interphase centrosomes to ensure their proper segregation in stem cells

The Journal of Cell Biology ◽

10.1083/jcb.201303141 ◽

2013 ◽

Vol 202 (7) ◽

pp. 1013-1022 ◽

Cited By ~ 42

Author(s):

Dorothy A. Lerit ◽

Nasser M. Rusan

Keyword(s):

Stem Cells ◽

Drosophila Melanogaster ◽

Cell Division ◽

Neural Stem Cells ◽

Asymmetric Cell Division ◽

Negative Regulator ◽

Daughter Cells ◽

Polo Kinase ◽

Central Brain ◽

Pericentriolar Material

Centrosomes determine the mitotic axis of asymmetrically dividing stem cells. Several studies have shown that the centrosomes of the Drosophila melanogaster central brain neural stem cells are themselves asymmetric, organizing varying levels of pericentriolar material and microtubules. This asymmetry produces one active and one inactive centrosome during interphase. We identify pericentrin-like protein (PLP) as a negative regulator of centrosome maturation and activity. We show that PLP is enriched on the inactive interphase centrosome, where it blocks recruitment of the master regulator of centrosome maturation, Polo kinase. Furthermore, we find that ectopic Centrobin expression influenced PLP levels on the basal centrosome, suggesting it may normally function to regulate PLP. Finally, we conclude that, although asymmetric centrosome maturation is not required for asymmetric cell division, it is required for proper centrosome segregation to the two daughter cells.

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Erratum to Walczak et al. Applicability and limitations of MR tracking of neural stem cells with asymmetric cell division and rapid turnover: The case of the shiverer dysmyelinated mouse brain. Magn Reson Med 2007;58:261–269.

Magnetic Resonance in Medicine ◽

10.1002/mrm.21412 ◽

2007 ◽

Vol 58 (6) ◽

pp. 1299-1299 ◽

Cited By ~ 2

Author(s):

P. Walczak ◽

D.A. Kedziorek ◽

A.A. Gilad ◽

B.P. Barnett ◽

J.W.M. Bulte

Keyword(s):

Stem Cells ◽

Cell Division ◽

Neural Stem Cells ◽

Mouse Brain ◽

Asymmetric Cell Division ◽

Rapid Turnover

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Phase Separation and Mechanical Forces in Regulating Asymmetric Cell Division of Neural Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms221910267 ◽

2021 ◽

Vol 22 (19) ◽

pp. 10267

Author(s):

Yiqing Zhang ◽

Heyang Wei ◽

Wenyu Wen

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Phase Separation ◽

Cell Division ◽

Neural Stem Cells ◽

Asymmetric Cell Division ◽

Stem Cell Population ◽

Mechanical Forces ◽

Major Mechanism ◽

Asymmetrically Distributed

Asymmetric cell division (ACD) of neural stem cells and progenitors not only renews the stem cell population but also ensures the normal development of the nervous system, producing various types of neurons with different shapes and functions in the brain. One major mechanism to achieve ACD is the asymmetric localization and uneven segregation of intracellular proteins and organelles into sibling cells. Recent studies have demonstrated that liquid-liquid phase separation (LLPS) provides a potential mechanism for the formation of membrane-less biomolecular condensates that are asymmetrically distributed on limited membrane regions. Moreover, mechanical forces have emerged as pivotal regulators of asymmetric neural stem cell division by generating sibling cell size asymmetry. In this review, we will summarize recent discoveries of ACD mechanisms driven by LLPS and mechanical forces.

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