The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Degrassi, Francesca; Damizia, Michela; Lavia, Patrizia

doi:10.3390/cells9010049

Cited by 20 publications

(24 citation statements)

References 139 publications

(164 reference statements)

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“…Over 25 loci are implicated in the etiology of human microcephaly and a majority of these encode mitotic regulators [15]. This rich human genetics has continued to support the long-standing model that mitotic defects in progenitors underlie microcephaly [45][46][47][48].…”

Section: Discussionmentioning

confidence: 95%

“…While autosomal recessive primary microcephaly is relatively rare, microcephaly syndromes are highly prevalent, affecting between 1 and 2% of the population. To date, autosomal recessive primary microcephaly has been linked to mutations in 25 loci [15]. Remarkably, the vast majority of these genes encode proteins associated with cell division [15].…”

Section: Introductionmentioning

confidence: 99%

“…To date, autosomal recessive primary microcephaly has been linked to mutations in 25 loci [15]. Remarkably, the vast majority of these genes encode proteins associated with cell division [15]. This has led to a long-standing hypothesis in the field that disruptions to mitosis explain microcephaly.…”

Section: Introductionmentioning

confidence: 99%

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Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

et al. 2019

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Background/Aims: Prenatal microcephaly is posited to arise from aberrant mitosis of neural progenitors, which disrupts both neuronal production and survival. Although microcephaly has both a genetic and environmental etiology, the mechanisms by which dysregulation of mitosis causes microcephaly are poorly understood. We previously discovered that prolonged mitosis of mouse neural progenitors, either ex vivo or in vitro, directly alters progeny cell fate, resulting in precocious differentiation and apoptosis. This raises questions as to whether prolonged progenitor mitosis affects cell fate and neurogenesis in vivo, and what are the underlying mechanisms? Methods/Results: Towards addressing these knowledge gaps, we developed an in vivo model of mitotic delay. This uses pharmacological inhibition to acutely and reversibly prolong mitosis during cortical development, and fluorescent dyes to label direct progeny. Using this model, we discovered that a causal relationship between mitotic delay of neural progenitors and altered progeny cell fate is evident in vivo. Using transcriptome analyses to investigate the state of delayed cells and their progeny, we uncovered potential molecular mechanisms by which prolonged mitosis induces altered cell fates, including DNA damage and p53 signaling. We then extended our studies to human neural progenitors, demonstrating that lengthened mitosis duration also directly alters neuronal cell fate. Conclusions: This study establishes a valuable new experimental paradigm towards understanding mechanisms whereby lengthened mitosis duration may explain some cases of microcephaly.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

et al. 2019

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“…MCPH is caused by a depletion of the NPC pool and death of neurons during embryonic development, both of which lead to the generation of fewer mature neurons in the developed cortex (Faheem et al , 2015). 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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“…It, thus, seems that MCPH24 phenotypes might be the result of several cellular perturbations, including chromosome congression defects and abnormal spindle assembly, which are essential for the apical migration of neuronal precursors and the architecture of the developing brain (Degrassi et al 2019).…”

Section: Nucleoporin 37 (Nup37/mcph24)mentioning

confidence: 99%

Primary microcephaly with an unstable genome

Peng

et al. 2020

GENOME INSTAB. DIS.

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Autosomal recessive primary microcephaly, also known as MCPH, is a rare genetic condition where infants are born with small heads and brains. The causes of MCPH are often unknown or unclear. To date, 25 genes have been found to be associated with MCPH. Most of these genes serve similar roles in maintaining genome stability, being associated with centrosome and spindle function, chromosome dynamics, cell cycle regulation, cell division, brain development, neurogenesis, and/or the DNA damage response. In this review, we classify MCPH-associated genes based on their known functions, and propose potential novel functions of MCPH genes in DNA replication and/or the DNA replication stress response, and tumorigenesis. This classification provides a novel perspective on the underlying causes of MCPH and a comprehensive reference for future research.

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The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Cited by 20 publications

References 139 publications

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

Acute Lengthening of Progenitor Mitosis Influences Progeny Fate during Cortical Development in vivo

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

Primary microcephaly with an unstable genome

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