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Morphological and functional aspects of progenitors perturbed in cortical malformations.

Bizzotto S, Francis F - Front Cell Neurosci (2015)

Bottom Line: We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons.The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type.Going beyond this, we discuss future directions that may provide new data in this expanding area.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMRS 839 Paris, France ; Sorbonne Universités, Université Pierre et Marie Curie Paris, France ; Institut du Fer à Moulin Paris, France.

ABSTRACT
In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.

No MeSH data available.


Related in: MedlinePlus

MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).
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Figure 1: MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).

Mentions: Cortical malformations (Figure 1) are usually detected during pregnancy (fetal ultrasound), and are obvious after birth due to developmental delay, epilepsy and intellectual deficits. In human, magnetic resonance imaging (MRI) is used to classify the defects and if a genetic origin is suspected, this classification directs potential genetic screens. New variants of these disorders, unexplained by known genes, are currently the subject of exome sequencing projects. Studies in the mouse, as well as in other organisms, try to model these disorders. Knockdown or knockout of genes of interest reveals the cellular mechanisms. Alternatively, mouse mutants arise spontaneously and their characterization subsequently helps reveal both new genes and mechanisms. In general there are many different forms of cortical malformation, and many variants in each category. This review aims not to be exhaustive, but to resume general notions related to the abnormal functioning of progenitor cells. We start here by briefly describing the malformations of interest at the morphological level. We then group different gene mutations, classifying by similar phenotypes observed in mouse mutants, and in so-doing, dissect different aspects of progenitor cell function. Finally, we discuss and integrate all this information in order to have a more global current view of the cellular mechanisms related to malformations.


Morphological and functional aspects of progenitors perturbed in cortical malformations.

Bizzotto S, Francis F - Front Cell Neurosci (2015)

MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4325918&req=5

Figure 1: MRI schemas of malformations. (A) Control brain, (B) Cobblestone lissencephaly, where neuronal overmigration (represented by gray patches at the surface of the brain) can arise due to breaks of the basement membrane. (C) Periventricular nodular heterotopia, some neurons (represented by gray nodules) remain stuck at the ventricular surface, most probably due to breaks and disorganization of the ventricular lining. (D) Microcephaly, several mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. In pure forms, brain architecture is relatively well-preserved, in other forms (microcephaly with simplified gyral pattern, MSGP, not shown), brain organization and cortical folds are also affected. (E) Globular or ribbon-like heterotopia, represented by gray globular masses. In this case the heterotopia starts at the level of the ventricles and fills up the white matter in some brain areas. The heterotopia can appear to have gyri. Modified from Francis et al. (2006).
Mentions: Cortical malformations (Figure 1) are usually detected during pregnancy (fetal ultrasound), and are obvious after birth due to developmental delay, epilepsy and intellectual deficits. In human, magnetic resonance imaging (MRI) is used to classify the defects and if a genetic origin is suspected, this classification directs potential genetic screens. New variants of these disorders, unexplained by known genes, are currently the subject of exome sequencing projects. Studies in the mouse, as well as in other organisms, try to model these disorders. Knockdown or knockout of genes of interest reveals the cellular mechanisms. Alternatively, mouse mutants arise spontaneously and their characterization subsequently helps reveal both new genes and mechanisms. In general there are many different forms of cortical malformation, and many variants in each category. This review aims not to be exhaustive, but to resume general notions related to the abnormal functioning of progenitor cells. We start here by briefly describing the malformations of interest at the morphological level. We then group different gene mutations, classifying by similar phenotypes observed in mouse mutants, and in so-doing, dissect different aspects of progenitor cell function. Finally, we discuss and integrate all this information in order to have a more global current view of the cellular mechanisms related to malformations.

Bottom Line: We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons.The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type.Going beyond this, we discuss future directions that may provide new data in this expanding area.

View Article: PubMed Central - PubMed

Affiliation: INSERM UMRS 839 Paris, France ; Sorbonne Universités, Université Pierre et Marie Curie Paris, France ; Institut du Fer à Moulin Paris, France.

ABSTRACT
In this review, we discuss molecular and cellular mechanisms important for the function of neuronal progenitors during development, revealed by their perturbation in different cortical malformations. We focus on a class of neuronal progenitors, radial glial cells (RGCs), which are renowned for their unique morphological and behavioral characteristics, constituting a key element during the development of the mammalian cerebral cortex. We describe how the particular morphology of these cells is related to their roles in the orchestration of cortical development and their influence on other progenitor types and post-mitotic neurons. Important for disease mechanisms, we overview what is currently known about RGC cellular components, cytoskeletal mechanisms, signaling pathways and cell cycle characteristics, focusing on how defects lead to abnormal development and cortical malformation phenotypes. The multiple recent entry points from human genetics and animal models are contributing to our understanding of this important cell type. Combining data from phenotypes in the mouse reveals molecules which potentially act in common pathways. Going beyond this, we discuss future directions that may provide new data in this expanding area.

No MeSH data available.


Related in: MedlinePlus