Centrosomes: The good and the bad for brain development

Marthiens, Véronique; Basto, Renata

doi:10.1111/boc.201900090

Cited by 27 publications

(26 citation statements)

References 165 publications

(218 reference statements)

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“…So far, MCPH has been linked to mutations in ~ 25 genes (Jayaraman et al , 2018; Degrassi et al , 2019). Remarkably, many of these genes encode proteins required for centrosome duplication, underscoring a critical role of these organelles in the production of normal neuronal populations in the cortex (Marthiens & Basto, 2020).…”

Section: Introductionmentioning

confidence: 99%

Centrosome defects cause microcephaly by activating the 53BP1‐USP28‐TP53 mitotic surveillance pathway

et al. 2020

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Mutations in centrosome genes deplete neural progenitor cells (NPCs) during brain development, causing microcephaly. While NPC attrition is linked to TP53-mediated cell death in several microcephaly models, how TP53 is activated remains unclear. In cultured cells, mitotic delays resulting from centrosome loss prevent the growth of unfit daughter cells by activating a pathway involving 53BP1, USP28, and TP53, termed the mitotic surveillance pathway. Whether this pathway is active in the developing brain is unknown. Here, we show that the depletion of centrosome proteins in NPCs prolongs mitosis and increases TP53-mediated apoptosis. Cell death after a delayed mitosis was rescued by inactivation of the mitotic surveillance pathway. Moreover, 53BP1 or USP28 deletion restored NPC proliferation and brain size without correcting the upstream centrosome defects or extended mitosis. By contrast, microcephaly caused by the loss of the non-centrosomal protein SMC5 is also TP53-dependent but is not rescued by loss of 53BP1 or USP28. Thus, we propose that mutations in centrosome genes cause microcephaly by delaying mitosis and pathologically activating the mitotic surveillance pathway in the developing brain.

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Section: Introductionmentioning

confidence: 99%

Centrosome defects cause microcephaly by activating the 53BP1‐USP28‐TP53 mitotic surveillance pathway

et al. 2020

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“…The centrosome plays a major role in the primary microtubule organization. Its dysfunction has a major impact on brain size and functionality, including ciliogenesis, suggesting a possible involvement in the glymphatic system ( Marthiens and Basto, 2020 ; Yang et al, 2021b ; Narita and Takeda, 2021 ). The centrosome is a complex organelle composed of two perpendicular cylindrical microtubule-based structures termed as the proximal and distal ends or centrioles.…”

Section: Human Genetic Studies Of Hydrocephalusmentioning

confidence: 99%

Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

Zhang

Guo

et al. 2022

Front. Genet.

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Hydrocephalus is a neurological condition due to the aberrant circulation and/or obstruction of cerebrospinal fluid (CSF) flow with consequent enlargement of cerebral ventricular cavities. However, it is noticed that a lot of patients may still go through symptomatic progression despite standard shunting procedures, suggesting that hydrocephalus is far more complicated than a simple CSF circulative/obstructive disorder. Growing evidence indicates that genetic factors play a fundamental role in the pathogenesis of some hydrocephalus. Although the genetic research of hydrocephalus in humans is limited, many genetic loci of hydrocephalus have been defined in animal models. In general, the molecular abnormalities involved in the pathogenesis of hydrocephalus include brain development and ependymal cell dysfunction, apoptosis, inflammation, free radical generation, blood flow, and cerebral metabolism. Moreover, recent studies have indicated that the molecular abnormalities relevant to aberrant cerebral glymphatic drainage turn into an attractive subject in the CSF circulation disorder. Furthermore, the prevalent risk factors could facilitate the development of hydrocephalus. In this review, we elicited some possible fundamental molecular mechanisms and facilitating risk factors involved in the pathogenesis of hydrocephalus, and aimed to widen the diagnosis and therapeutic strategies for hydrocephalus management. Such knowledge could be used to improve patient care in different ways, such as early precise diagnosis and effective therapeutic regimens.

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“…The following section summarizes aspects of such processes that are crucial for neurogenesis, neuronal maintenance and brain formation. For more detailed information, we point the readers to excellent recent reviews that cover individual aspects in more depth (Chen & Yamashita, 2021; Hasenpusch‐Theil & Theil, 2021; Marthiens & Basto, 2020; Park et al., 2019; Saade et al., 2018; Wilsch‐Brauninger & Huttner, 2021).…”

Section: Centrosomes and Cilia In The Developing Brainmentioning

confidence: 99%

DNA Replication proteins in primary microcephaly syndromes

Tingler

Philipp

Burkhalter

2022

Biology of the Cell

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Improper expansion of neural stem and progenitor cells during brain development manifests in primary microcephaly. This disease is characterized by a reduced head circumference, which correlates with a reduction in brain size. This often corresponds to a general underdevelopment of the brain and entails cognitive, behavioral and motoric retardation. In the past decade significant research efforts have been undertaken to identify genes and the molecular mechanisms underlying microcephaly. One such gene set encompasses factors required for DNA replication. Intriguingly, a growing body of evidence indicates that a substantial number of these genes mediate faithful centrosome and cilium function in addition to their canonical function in genome duplication. Here, we summarize, which DNA replication factors are associated with microcephaly syndromes and to which extent they impact on centrosomes and cilia.

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Centrosomes: The good and the bad for brain development

Cited by 27 publications

References 165 publications

Centrosome defects cause microcephaly by activating the 53BP1‐USP28‐TP53 mitotic surveillance pathway

Centrosome defects cause microcephaly by activating the 53BP1‐USP28‐TP53 mitotic surveillance pathway

Molecular Mechanisms and Risk Factors for the Pathogenesis of Hydrocephalus

DNA Replication proteins in primary microcephaly syndromes

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