Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype

Javed, Attya Omer; Li, Yun; Muffat, Julien; Su, Kuan-Chung; Cohen, Malkiel A.; Lungjangwa, Tenzin; Aubourg, Patrick; Cheeseman, Iain M.; Jaenisch, Rudolf

doi:10.1016/j.celrep.2018.09.032

Cited by 35 publications

(33 citation statements)

References 43 publications

(69 reference statements)

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“…This raises the question as to why mutations that mostly disrupt the coding-sequences of genes temporally dynamic in multiple organs lead to diseases that are organ-specific. A number of different factors may explain this phenomenon, including alternative splicing (e.g., mutations may affect only organ-specific isoforms) [26], functional redundancy [25], and/or dependency on the characteristics of specific cell types (e.g., protein-misfolding diseases in long-lived neurons). It has also been suggested that pathologies tend to be associated with the organ where the genes display elevated expression [24].…”

Section: Resultsmentioning

confidence: 99%

Developmental gene expression differences between humans and mammalian models

Cardoso-Moreira

Velten

Mort

et al. 2019

Preprint

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14Identifying the molecular programs underlying human organ development and how they differ from 15 those in model species will advance our understanding of human health and disease. 16 Developmental gene expression profiles provide a window into the genes underlying organ 17 development as well as a direct means to compare them across species. We use a transcriptomic 18 resource for mammalian organ development to characterize the temporal profiles of human genes 19 associated with distinct disease classes and to determine, for each human gene, the similarity of its 20 spatiotemporal expression with its orthologs in rhesus macaque, mouse, rat and rabbit. We find 21 that half of human genes differ from their mouse orthologs in their temporal trajectories. These 22 include more than 200 disease genes associated with brain, heart and liver disease, for which mouse 23 models should undergo extra scrutiny. We provide a new resource that evaluates for every human 24 gene its suitability to be modeled in different mammalian species. 25 26 27 28 42 rhesus macaques) are routinely used as models of both normal human development and human 43 disease because it is generally assumed that the genes and regulatory networks underlying 44 development are largely conserved across these species. While this is generally true, there are also 45 critical differences between species during development, which underlie the large diversity of 46 3 mammalian organ phenotypes [1-6,8]. Identifying the commonalities and differences between the 47 genetic programs underlying organ development in different mammalian species is therefore 48 paramount for assessing the translatability of knowledge obtained from mammalian models to 49 understand human health and disease. Critically, gene expression profiles can be directly compared 50 between species, especially when they are derived from matching cells/organs and developmental 51 stages. Gene expression therefore offers a direct means to evaluate similarities and differences 52 between species in organ developmental programs. While the relationship between gene 53 expression and phenotypes is not linear, identifying when and where gene expression differs 54 between humans and other species will help identify the conditions (i.e., developmental stages, 55 organs, genes) under which model species may not be well suited to model human development 56 and disease. 57 58Here, we take advantage of a developmental gene expression resource [13], which densely covers 59 the development of seven major organs in humans and other mammals, to characterize the 60 spatiotemporal profiles of human disease genes and gain new insights into the symptomatology of 61 diseases. We also determine for each human gene (including disease-associated genes) the 62 similarity of its spatiotemporal expression with that of its orthologs in mouse, rat, rabbit and rhesus 63 macaque. Our analyses and datasets therefore provide a new resource for assessing the suitability 64 of different mammalian species to model the action ...

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Section: Resultsmentioning

confidence: 99%

Developmental gene expression differences between humans and mammalian models

Cardoso-Moreira

Velten

Mort

et al. 2019

Preprint

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“…Mutant neural progenitors underwent a lengthening of mitosis that was associated with cytokinesis failure, cell death, and premature differentiation toward astrocytes and neurons. Finally, using 3D neural spheroids, the authors showed a reduction in the size of mutant spheroids, which could be attributed to reduced proliferation and premature differentiation of the neural progenitors [102]. Although differences in KNL1 protein levels had not been reported in patients fibroblasts or lymphocytes in previous work [51], decreased levels of KNL1 were found to be present in mutant neural progenitors, possibly reflecting neural-specific differences in KNL1 mRNA processing.…”

Section: Casc5/knlmentioning

confidence: 83%

“…Although differences in KNL1 protein levels had not been reported in patients fibroblasts or lymphocytes in previous work [51], decreased levels of KNL1 were found to be present in mutant neural progenitors, possibly reflecting neural-specific differences in KNL1 mRNA processing. In contrast, mutant fibroblasts and mutant neural crest cells showed no reduction in KNL1 levels and no defective growth, demonstrating that the KNL1 mutation affects only neural progenitors, which was possibly due to the higher levels of splicing proteins that were identified in these cells [102].…”

Section: Casc5/knlmentioning

confidence: 92%

“…The conditional deletion of KNL1 in neural progenitor cells triggered a rapid P53-dependent apoptotic response and neural progenitor loss. This was associated A definite hint on the brain-specific phenotype of KNL mutations was provided in a study that used the in vitro differentiation of human embryonic stem cells to monitor the effect of the mutation leading to exon 19 skipping on neuronal development [102]. The missense mutation was targeted by CRISPR/CAS9 editing to Human Embryonic Stem Cells (hESCs) that were then differentiated into neural progenitors.…”

Section: Casc5/knlmentioning

confidence: 99%

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The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Degrassi

Damizia

Lavia

2019

Cells

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Regulators of mitotic division, when dysfunctional or expressed in a deregulated manner (over- or underexpressed) in somatic cells, cause chromosome instability, which is a predisposing condition to cancer that is associated with unrestricted proliferation. Genes encoding mitotic regulators are growingly implicated in neurodevelopmental diseases. Here, we briefly summarize existing knowledge on how microcephaly-related mitotic genes operate in the control of chromosome segregation during mitosis in somatic cells, with a special focus on the role of kinetochore factors. Then, we review evidence implicating mitotic apparatus- and kinetochore-resident factors in the origin of congenital microcephaly. We discuss data emerging from these works, which suggest a critical role of correct mitotic division in controlling neuronal cell proliferation and shaping the architecture of the central nervous system.

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“…Another possibility may lie in alternative splicing. The brain undergoes the most alternative splicing events than any other tissue and expresses the largest number of splicing factor genes (170). This means that the brain produces more diverse protein isoforms than other tissue types.…”

Section: Remaining Questionsmentioning

confidence: 99%

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

2020

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Autosomal recessive primary microcephaly (MCPH; "small head syndrome") is a rare, heterogeneous disease arising from the decreased production of neurons during brain development. As of August 2020, the Online Mendelian Inheritance in Man (OMIM) database lists 25 genes (involved in molecular processes such as centriole biogenesis, microtubule dynamics, spindle positioning, DNA repair, transcriptional regulation, Wnt signaling, and cell cycle checkpoints) that are implicated in causing MCPH. Many of these 25 genes were only discovered in the last 10 years following advances in exome and genome sequencing that have improved our ability to identify disease-causing variants. Despite these advances, many patients still lack a genetic diagnosis. This demonstrates a need to understand in greater detail the molecular mechanisms and genetics underlying MCPH. Here, we briefly review the molecular functions of each MCPH gene and how their loss disrupts the neurogenesis program, ultimately demonstrating that microcephaly arises from cell cycle dysregulation. We also explore the current issues in the genetic basis and clinical presentation of MCPH as additional avenues of improving gene/variant prioritization. Ultimately, we illustrate that the detailed exploration of the etiology and inheritance of MCPH improves the predictive power in identifying previously unknown MCPH candidates and diagnosing microcephalic patients.

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Microcephaly Modeling of Kinetochore Mutation Reveals a Brain-Specific Phenotype

Cited by 35 publications

References 43 publications

Developmental gene expression differences between humans and mammalian models

Developmental gene expression differences between humans and mammalian models

The Mitotic Apparatus and Kinetochores in Microcephaly and Neurodevelopmental Diseases

Dissecting the Genetic and Etiological Causes of Primary Microcephaly

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