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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

RGC mechanisms leading to mouse malformations. (A) Control situation, apical progenitors (containing blue nuclei) divide by interkinetic nuclear migration (INM) in the VZ, neurons (burgundy nuclei) migrate radially on RGC basal processes across the IZ, to settle in the CP. Cajal Retzius cells (ovals) present in the MZ secrete signals to the migrating neurons. End-feet of RGC basal processes receive signals from ECM molecules in the BM close to the pial surface. (B) Cobblestone lissencephaly phenotype, in this case some RGC basal processes are not well attached to the pial surface, possible breaks in the BM potentially cause neurons (burgundy nuclei at the surface of the brain) in some regions to overmigrate into the meningeal space. (C) Periventricular disorganization, some neurons (burgundy nuclei) remain stuck at the ventricular surface, most probably due to breaks in the ventricular lining where apical end-feet of RGCs normally attach. (D) Microcephaly phenotype, two potential mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. Some mouse models suggest that premature differentiation of progenitors into post-mitotic neurons (burgundy nuclei within radially migrating neuron close to VZ) depletes the progenitor pool (represented by red cross over blue nuclei in VZ). Other studies show instead increased cell death of abnormal progenitors (red cross over blue nuclei present in IZ). (E) Globular heterotopia (e.g., HeCo mice), in this case a proportion of apical progenitors detach from the ventricular surface (represented by blue nuclei without apical attachment to the ventricular lining) and retain proliferation capacity, providing a local source of neurons in the IZ (burgundy nuclei). A subcortical heterotopia subsequently arises. VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone; BM, basement membrane.
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Figure 2: RGC mechanisms leading to mouse malformations. (A) Control situation, apical progenitors (containing blue nuclei) divide by interkinetic nuclear migration (INM) in the VZ, neurons (burgundy nuclei) migrate radially on RGC basal processes across the IZ, to settle in the CP. Cajal Retzius cells (ovals) present in the MZ secrete signals to the migrating neurons. End-feet of RGC basal processes receive signals from ECM molecules in the BM close to the pial surface. (B) Cobblestone lissencephaly phenotype, in this case some RGC basal processes are not well attached to the pial surface, possible breaks in the BM potentially cause neurons (burgundy nuclei at the surface of the brain) in some regions to overmigrate into the meningeal space. (C) Periventricular disorganization, some neurons (burgundy nuclei) remain stuck at the ventricular surface, most probably due to breaks in the ventricular lining where apical end-feet of RGCs normally attach. (D) Microcephaly phenotype, two potential mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. Some mouse models suggest that premature differentiation of progenitors into post-mitotic neurons (burgundy nuclei within radially migrating neuron close to VZ) depletes the progenitor pool (represented by red cross over blue nuclei in VZ). Other studies show instead increased cell death of abnormal progenitors (red cross over blue nuclei present in IZ). (E) Globular heterotopia (e.g., HeCo mice), in this case a proportion of apical progenitors detach from the ventricular surface (represented by blue nuclei without apical attachment to the ventricular lining) and retain proliferation capacity, providing a local source of neurons in the IZ (burgundy nuclei). A subcortical heterotopia subsequently arises. VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone; BM, basement membrane.

Mentions: As RGCs present a very specialized morphology and dynamics, which are strictly linked with the function they exert during cortex development, every minor perturbation involving their structure or behavior is susceptible to lead to major developmental problems. Indeed, numerous genes coding for proteins influencing RGC morphology and function have been found mutated in mouse models and in cortical malformation patients. We try to bring together here mouse mutant data related to these genes (also resumed in Table 2), classifying these data by different RGC compartments and cellular mechanisms (resumed in Figures 2, 3).


Morphological and functional aspects of progenitors perturbed in cortical malformations.

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

RGC mechanisms leading to mouse malformations. (A) Control situation, apical progenitors (containing blue nuclei) divide by interkinetic nuclear migration (INM) in the VZ, neurons (burgundy nuclei) migrate radially on RGC basal processes across the IZ, to settle in the CP. Cajal Retzius cells (ovals) present in the MZ secrete signals to the migrating neurons. End-feet of RGC basal processes receive signals from ECM molecules in the BM close to the pial surface. (B) Cobblestone lissencephaly phenotype, in this case some RGC basal processes are not well attached to the pial surface, possible breaks in the BM potentially cause neurons (burgundy nuclei at the surface of the brain) in some regions to overmigrate into the meningeal space. (C) Periventricular disorganization, some neurons (burgundy nuclei) remain stuck at the ventricular surface, most probably due to breaks in the ventricular lining where apical end-feet of RGCs normally attach. (D) Microcephaly phenotype, two potential mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. Some mouse models suggest that premature differentiation of progenitors into post-mitotic neurons (burgundy nuclei within radially migrating neuron close to VZ) depletes the progenitor pool (represented by red cross over blue nuclei in VZ). Other studies show instead increased cell death of abnormal progenitors (red cross over blue nuclei present in IZ). (E) Globular heterotopia (e.g., HeCo mice), in this case a proportion of apical progenitors detach from the ventricular surface (represented by blue nuclei without apical attachment to the ventricular lining) and retain proliferation capacity, providing a local source of neurons in the IZ (burgundy nuclei). A subcortical heterotopia subsequently arises. VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone; BM, basement membrane.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: RGC mechanisms leading to mouse malformations. (A) Control situation, apical progenitors (containing blue nuclei) divide by interkinetic nuclear migration (INM) in the VZ, neurons (burgundy nuclei) migrate radially on RGC basal processes across the IZ, to settle in the CP. Cajal Retzius cells (ovals) present in the MZ secrete signals to the migrating neurons. End-feet of RGC basal processes receive signals from ECM molecules in the BM close to the pial surface. (B) Cobblestone lissencephaly phenotype, in this case some RGC basal processes are not well attached to the pial surface, possible breaks in the BM potentially cause neurons (burgundy nuclei at the surface of the brain) in some regions to overmigrate into the meningeal space. (C) Periventricular disorganization, some neurons (burgundy nuclei) remain stuck at the ventricular surface, most probably due to breaks in the ventricular lining where apical end-feet of RGCs normally attach. (D) Microcephaly phenotype, two potential mechanisms may give rise to this malformation leading to a greatly reduced size of the brain. Some mouse models suggest that premature differentiation of progenitors into post-mitotic neurons (burgundy nuclei within radially migrating neuron close to VZ) depletes the progenitor pool (represented by red cross over blue nuclei in VZ). Other studies show instead increased cell death of abnormal progenitors (red cross over blue nuclei present in IZ). (E) Globular heterotopia (e.g., HeCo mice), in this case a proportion of apical progenitors detach from the ventricular surface (represented by blue nuclei without apical attachment to the ventricular lining) and retain proliferation capacity, providing a local source of neurons in the IZ (burgundy nuclei). A subcortical heterotopia subsequently arises. VZ, ventricular zone; IZ, intermediate zone; CP, cortical plate; MZ, marginal zone; BM, basement membrane.
Mentions: As RGCs present a very specialized morphology and dynamics, which are strictly linked with the function they exert during cortex development, every minor perturbation involving their structure or behavior is susceptible to lead to major developmental problems. Indeed, numerous genes coding for proteins influencing RGC morphology and function have been found mutated in mouse models and in cortical malformation patients. We try to bring together here mouse mutant data related to these genes (also resumed in Table 2), classifying these data by different RGC compartments and cellular mechanisms (resumed in Figures 2, 3).

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