We have got you ‘covered’: how the meninges control brain development

doi:10.1016/j.gde.2010.12.005

Current Opinion in Genetics & Development

Volume 21, Issue 3, June 2011, Pages 249-255

https://doi.org/10.1016/j.gde.2010.12.005 Get rights and content

The meninges have traditionally been viewed as specialized membranes surrounding and protecting the adult brain from injury. However, there is increasing evidence that the fetal meninges play important roles during brain development. Through the release of diffusible factors, the meninges influence the proliferative and migratory behaviors of neural progenitors and neurons in the forebrain and hindbrain. Meningeal cells also secrete and organize the pial basement membrane (BM), a critical anchor point for the radially oriented fibers of neuroepithelial stem cells. With its emerging role in brain development, the potential that defects in meningeal development may underlie certain congenital brain abnormalities in humans should be considered. In this review, we will discuss what is known about assembly of the fetal meninges and review the role of meningeal-derived proteins in mouse and human brain development.

Section snippets

Origin and structure of the fetal meninges

The first, primitive layer of meningeal cells is identifiable early in neural development: in chick, at HH15 (embryonic day or E2) [1], in mouse between E9 and E10 [2] and in human, Carnegie stage 15 or ∼4th gestational week [3]. In the forebrain, this initial layer of meningeal cells is part of a wave of rostrally migrating cranial neural crest cells originating from the diencephalic neural crest [4]. In contrast, the meninges surrounding the midbrain, hindbrain, and spinal cord originate from

Secreted factors from the meninges regulate neural migration and positioning

The meninges, with their close proximity to the developing brain, are strategically positioned to provide short-range cues to neural cells located in the outer layer of developing brain structures. One example of this type of signal is Cxcl12 (aka SDF-1), which mediates chemoattraction of multiple cell types via binding to its receptors Cxcr4 and Cxcr7 (for review see [16]). In the forebrain and cerebellum specifically, meningeal-derived Cxcl12 plays an important role in neuronal migration and

Retinoic acid produced by the meninges regulates forebrain and hindbrain development

Retinoic acid (RA) is a lipophilic, small molecule critical for early events in CNS development, including neural tube closure and early forebrain patterning [36, 37]. The meninges express high levels of RA synthesizing enzymes [38, 39] and have proven to be in important source of this morphogen during brain development.

Neocortical development starts with an expansion phase where radial neural progenitors go through symmetric, self-renewing divisions. As cortical neuron generation begins,

Maintenance of the pial basement membrane by the meninges

Immediately below the pial meningeal layer is the extracellular matrix-enriched BM. The pial BM acts as both an anchor point for the endfeet of radial processes that originate from neuronal progenitors cells residing in the ventricular zone (VZ) and as a physical barrier to migrating neurons. During both cortical and cerebellar development, the radial processes provide a migratory scaffold for neurons that helps ensure correct cellular layering. Genetic ablation of components of the pial BM [42

Meninges and neurodevelopmental disorders: potential connection?

Meningeal-derived factors are involved in several, critical developmental events in the brain. This raises the possibility that defects in meningeal development or function, either through genetic mutation or through damage to the meninges in utero, may underlie certain neurodevelopmental disorders in humans. Recently, some cases of Dandy-Walker Syndrome, characterized by cerebellar hypoplasia and hydrocephaly, were linked to FOXC1 heterozygosity with small chromosomal deletions (6p25.3-FOXC1)

Conclusions

Studies over the last few years have made clear that the meninges are far more than strictly a protective layer in the adult tasked with the resorption of circulating CSF. It is now clear that the forebrain and hindbrain meninges serve as a signaling center coordinating developmental events between the cortex and the skull by releasing a variety of secreted factors that instruct surrounding tissues in the course of their developmental programs. In the case of the forebrain, where the meninges

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

Acknowledgements

This work was supported by NIDA R01 DA017627 (SJP), the Glenn W. Johnson Memorial Endowment (SJP) and NINDS K99 NS070920 (JAS).

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View full text

We have got you ‘covered’: how the meninges control brain development

Section snippets

Origin and structure of the fetal meninges

Secreted factors from the meninges regulate neural migration and positioning

Retinoic acid produced by the meninges regulates forebrain and hindbrain development

Maintenance of the pial basement membrane by the meninges

Meninges and neurodevelopmental disorders: potential connection?

Conclusions

References and recommended reading

Acknowledgements

Dev Biol

Dev Biol

Dev Biol

Cell

Leukemia

Nat Neurosci

Development

J Neurocytol

Ann Neurol

Anterior cephalic neural crest is required for forebrain viability

Development

Developmental morphology of the subarachnoid space and contiguous structures in the mouse

Am J Anat

The meninges in human development

J Neuropathol Exp Neurol

The contribution made by cells from a single somite to tissues within a body segment and assessment of their integration with similar cells from adjacent segments

Development

The developmental fate of the cephalic mesoderm in quail-chick chimeras

Development

Cortical dysplasia and skull defects in mice with a Foxc1 allele reveal the role of meningeal differentiation in regulating cortical development

Proc Natl Acad Sci U S A

Integration of FGF and TWIST in calvarial bone and suture development

Development

Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault

Development

Congenital hydrocephalus in the mouse, a case of spurious pleiotropism

J Genet

Impaired meningeal development in association with apical expansion of calvarial bone osteogenesis in the Foxc1 mutant

J Anat

Retinoic acid from the meninges regulates cortical neuron generation

Cell

Massive loss of Cajal-Retzius cells does not disrupt neocortical layer order

Development

Multiple origins of Cajal-Retzius cells at the borders of the developing pallium

Nat Neurosci

A transgenic marker mouse line labels Cajal-Retzius cells from the cortical hem and thalamocortical axons

Brain Res

Role of reelin in the development and maintenance of cortical lamination

J Neural Transm

Stromal-derived factor-1 (CXCL12) regulates laminar position of Cajal-Retzius cells in normal and dysplastic brains

J Neurosci

CXCR4 regulates interneuron migration in the developing neocortex

J Neurosci

Molecular interaction between projection neuron precursors and invading interneurons via stromal-derived factor 1 (CXCL12)/CXCR4 signaling in the cortical subventricular zone/intermediate zone

J Neurosci

Chemokine signaling controls intracortical migration and final distribution of GABAergic interneurons

J Neurosci