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Cells
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Cellular Mechanisms of Microcephaly
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Cellular Mechanisms of Microcephaly

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (13 September 2021) | Viewed by 19310

Special Issue Editors

Dr. Vincent El Ghouzzi

E-Mail Website
Guest Editor
NeuroDiderot, INSERM, Université de Paris, Paris, France
Interests: brain development; primary and postnatal microcephaly; neural progenitors; neuronal differentiation; membrane trafficking; golgi apparatus
Dr. Veronique Marthiens

E-Mail Website
Guest Editor
Biology of Centrosomes and Genetic Instability Laboratory, Institut Curie, PSL Research University, CNRS, Paris, France
Interests: embryonic neural stem cell biology; brain development; primary microcephaly; centrosome biology; mitotic defects

Special Issue Information

Dear Colleagues,

How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and humans’ place in the animal kingdom. Microcephaly, literally “small brain”, is one of the most frequent neurological signs encountered in neurodevelopmental disorders and reflects a failure in the process of brain growth and/or maturation. Microcephalies detected at birth or during pregnancy reflect defects that occurred during fetal development and are called primary or congenital microcephalies. On the other hand, secondary microcephalies that appear progressively during infancy or childhood rather result from postnatal defects.

The last two decades have seen the description of an increasing number of genetic causes or environmental insults, including viral infections during pregnancy that lead to congenital or postnatal microcephaly, alone or in association with other clinical features. Patients affected by microcephaly often display intellectual disability that strongly affects their educational and social life. If rodents, ferrets, and primates are commonly used as models, human cerebral organoids now appear as promising alternative in vitro models to investigate microcephaly-related disorders. Depletion of the embryonic neural stem cell population is at the basis of fetal brain size reduction, and mechanisms reported so far in the literature include defects in cell cycle and mitotic progression, chromosome number and/or integrity. Alternative pathophysiological mechanisms that affect neuronal polarization, vesicular trafficking, cell stress or autophagy are currently emerging as leading causes of microcephaly, including postnatal microcephalies. In addition to harms to neural stem cells, neuronal and glial maturation insults appear as important in regulating the size of the brain.

This Special Issue of Cells will focus on the cellular mechanisms that trigger microcephalies as a tribute to highlight and discuss the many different developmental harms and pathophysiological mechanisms that lead to brain size and homeostasis deregulation. The aim of this special issue is to bridge together our current knowledge of prenatal and postnatal microcephalies. We encourage original research articles, communications, reviews, or concept papers highlighting all aspects of microcephaly with a special interest in the underlying mechanisms at the basis of brain size reduction and disease modeling. We look forward to receiving your contributions.

Dr. Vincent El Ghouzzi
Dr. Veronique Marthiens
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Primary (congenital) microcephaly
  • Acquired (postnatal) microcephaly
  • Brain development
  • Neurogenesis, cell division
  • Identification of new causing mutations
  • Pathophysiological mechanisms leading to neural stem cell loss
  • Cellular mechanisms leading to neuronal and glial maturation insults
  • Microcephaly modeling

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Published Papers (5 papers)

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Research

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13 pages, 3626 KiB  
Article
Human Microcephaly Protein RTTN Is Required for Proper Mitotic Progression and Correct Spindle Position
by En-Ju Chou and Tang K. Tang
Cells 2021, 10(6), 1441; https://doi.org/10.3390/cells10061441 - 9 Jun 2021
Cited by 4 | Viewed by 3368
Abstract
Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the [...] Read more.
Autosomal recessive primary microcephaly (MCPH) is a complex neurodevelopmental disorder characterized by a small brain size with mild to moderate intellectual disability. We previously demonstrated that human microcephaly RTTN played an important role in regulating centriole duplication during interphase, but the role of RTTN in mitosis is not fully understood. Here, we show that RTTN is required for normal mitotic progression and correct spindle position. The depletion of RTTN induces the dispersion of the pericentriolar protein γ-tubulin and multiple mitotic abnormalities, including monopolar, abnormal bipolar, and multipolar spindles. Importantly, the loss of RTTN altered NuMA/p150Glued congression to the spindle poles, perturbed NuMA cortical localization, and reduced the number and the length of astral microtubules. Together, our results provide a new insight into how RTTN functions in mitosis. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Microcephaly)
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Review

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34 pages, 2536 KiB  
Review
Genetic Primary Microcephalies: When Centrosome Dysfunction Dictates Brain and Body Size
by Sarah Farcy, Hassina Hachour, Nadia Bahi-Buisson and Sandrine Passemard
Cells 2023, 12(13), 1807; https://doi.org/10.3390/cells12131807 - 7 Jul 2023
Cited by 3 | Viewed by 2577
Abstract
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., [...] Read more.
Primary microcephalies (PMs) are defects in brain growth that are detectable at or before birth and are responsible for neurodevelopmental disorders. Most are caused by biallelic or, more rarely, dominant mutations in one of the likely hundreds of genes encoding PM proteins, i.e., ubiquitous centrosome or microtubule-associated proteins required for the division of neural progenitor cells in the embryonic brain. Here, we provide an overview of the different types of PMs, i.e., isolated PMs with or without malformations of cortical development and PMs associated with short stature (microcephalic dwarfism) or sensorineural disorders. We present an overview of the genetic, developmental, neurological, and cognitive aspects characterizing the most representative PMs. The analysis of phenotypic similarities and differences among patients has led scientists to elucidate the roles of these PM proteins in humans. Phenotypic similarities indicate possible redundant functions of a few of these proteins, such as ASPM and WDR62, which play roles only in determining brain size and structure. However, the protein pericentrin (PCNT) is equally required for determining brain and body size. Other PM proteins perform both functions, albeit to different degrees. Finally, by comparing phenotypes, we considered the interrelationships among these proteins. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Microcephaly)
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18 pages, 395 KiB  
Review
Congenital Microcephaly: A Debate on Diagnostic Challenges and Etiological Paradigm of the Shift from Isolated/Non-Syndromic to Syndromic Microcephaly
by Maria Asif, Uzma Abdullah, Peter Nürnberg, Sigrid Tinschert and Muhammad Sajid Hussain
Cells 2023, 12(4), 642; https://doi.org/10.3390/cells12040642 - 16 Feb 2023
Cited by 4 | Viewed by 2644
Abstract
Congenital microcephaly (CM) exhibits broad clinical and genetic heterogeneity and is thus categorized into several subtypes. However, the recent bloom of disease–gene discoveries has revealed more overlaps than differences in the underlying genetic architecture for these clinical sub-categories, complicating the differential diagnosis. Moreover, [...] Read more.
Congenital microcephaly (CM) exhibits broad clinical and genetic heterogeneity and is thus categorized into several subtypes. However, the recent bloom of disease–gene discoveries has revealed more overlaps than differences in the underlying genetic architecture for these clinical sub-categories, complicating the differential diagnosis. Moreover, the mechanism of the paradigm shift from a brain-restricted to a multi-organ phenotype is only vaguely understood. This review article highlights the critical factors considered while defining CM subtypes. It also presents possible arguments on long-standing questions of the brain-specific nature of CM caused by a dysfunction of the ubiquitously expressed proteins. We argue that brain-specific splicing events and organ-restricted protein expression may contribute in part to disparate clinical manifestations. We also highlight the role of genetic modifiers and de novo variants in the multi-organ phenotype of CM and emphasize their consideration in molecular characterization. This review thus attempts to expand our understanding of the phenotypic and etiological variability in CM and invites the development of more comprehensive guidelines. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Microcephaly)
16 pages, 720 KiB  
Review
Cortical Organoids to Model Microcephaly
by Sarah Farcy, Alexandra Albert, Pierre Gressens, Alexandre D. Baffet and Vincent El Ghouzzi
Cells 2022, 11(14), 2135; https://doi.org/10.3390/cells11142135 - 7 Jul 2022
Cited by 4 | Viewed by 3855
Abstract
How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man’s place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, [...] Read more.
How the brain develops and achieves its final size is a fascinating issue that questions cortical evolution across species and man’s place in the animal kingdom. Although animal models have so far been highly valuable in understanding the key steps of cortical development, many human specificities call for appropriate models. In particular, microcephaly, a neurodevelopmental disorder that is characterized by a smaller head circumference has been challenging to model in mice, which often do not fully recapitulate the human phenotype. The relatively recent development of brain organoid technology from induced pluripotent stem cells (iPSCs) now makes it possible to model human microcephaly, both due to genetic and environmental origins, and to generate developing cortical tissue from the patients themselves. These 3D tissues rely on iPSCs differentiation into cortical progenitors that self-organize into neuroepithelial rosettes mimicking the earliest stages of human neurogenesis in vitro. Over the last ten years, numerous protocols have been developed to control the identity of the induced brain areas, the reproducibility of the experiments and the longevity of the cultures, allowing analysis of the later stages. In this review, we describe the different approaches that instruct human iPSCs to form cortical organoids, summarize the different microcephalic conditions that have so far been modeled by organoids, and discuss the relevance of this model to decipher the cellular and molecular mechanisms of primary and secondary microcephalies. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Microcephaly)
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15 pages, 286 KiB  
Review
Human-Specific Genes, Cortical Progenitor Cells, and Microcephaly
by Michael Heide and Wieland B. Huttner
Cells 2021, 10(5), 1209; https://doi.org/10.3390/cells10051209 - 15 May 2021
Cited by 29 | Viewed by 5506
Abstract
Over the past few years, human-specific genes have received increasing attention as potential major contributors responsible for the 3-fold difference in brain size between human and chimpanzee. Accordingly, mutations affecting these genes may lead to a reduction in human brain size and therefore, [...] Read more.
Over the past few years, human-specific genes have received increasing attention as potential major contributors responsible for the 3-fold difference in brain size between human and chimpanzee. Accordingly, mutations affecting these genes may lead to a reduction in human brain size and therefore, may cause or contribute to microcephaly. In this review, we will concentrate, within the brain, on the cerebral cortex, the seat of our higher cognitive abilities, and focus on the human-specific gene ARHGAP11B and on the gene family comprising the three human-specific genes NOTCH2NLA, -B, and -C. These genes are thought to have significantly contributed to the expansion of the cerebral cortex during human evolution. We will summarize the evolution of these genes, as well as their expression and functional role during human cortical development, and discuss their potential relevance for microcephaly. Furthermore, we will give an overview of other human-specific genes that are expressed during fetal human cortical development. We will discuss the potential involvement of these genes in microcephaly and how these genes could be studied functionally to identify a possible role in microcephaly. Full article
(This article belongs to the Special Issue Cellular Mechanisms of Microcephaly)
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