Brain Organization and Human Diseases

Abstract

The cortex is a highly organized structure that develops from the caudal regions of the segmented neural tube. Its spatial organization sets the stage for future functional arealization. Here, we suggest using a developmental perspective to describe and understand the etiology of common cortical malformations and their manifestation in the human brain.

Keywords: cortical development; forebrain; holoprosencephaly; lissencephaly; neuronal migration; signaling factors; telencephalon.

Figure 1

Schematic presentation of the events leading to forebrain formation. (a) Rostro-lateral representation of the neural plate as it folds and fuses at the midline to form the neural tube. The anterior neural ridge (ANR), shown in purple, is an organizer of the forebrain. Positioned at the most rostral part of the neural plate, its signaling will promote the formation of the future forebrain structure, the prosencephalon. Modified from [6]. (b) The primary vesicles appear in the fourth week of development and introduce three morphological segments of the brain: the prosencephalon, the mesencephalon, and the rhombencephalon. By the following week, the prosencephalon will further subdivide into the future forebrain structures: the anterior neural tube, the two telencephalon vesicles, and the diencephalon. (c) Sources of key morphogens are indicated; FGFs in green, BMPs and WNTs in red, SHH in yellow. The positions of the hem, anti-hem, and ganglionic eminences are indicated with black lines. Modified from [7].

Figure 2

The neuroepithelium and neuronal migration. Left, schematic presentation of the early neuroepithelium, showing interkinetic nuclear motility and asymmetric cell division leading to the formation of two daughter cells, a progenitor and a migrating neuron. Right, Later stages of brain development show three proliferative areas, the ventricular zone (VZ), the inner subventricular zone (iSVZ), and the outer subventricular zone (oSVZ). Different types of progenitors can be detected in the proliferative zones, radial glia, intermediate progenitors, and basal radial glia. Migrating neurons can be seen in the intermediate zone (IZ). The pyramidal neurons are organized in layers in the forming cortical plate (CP) based on their birth date. Cajal–Retzius cells that are born the earliest are detected in the marginal zone (MZ). Migrating interneurons are visible in two migratory streams.

Figure 3

Signalling pathways involved in holoprosencephaly. (a) SHH signaling pathway. (b) BMP antagonists TSG/CHD/NOG suppress the activation of BMP downstream effectors. (c) Nodal signaling leads to the phosphorylation of smad2/3, which translocates to the nucleus, where it is thought to interact with ZIC2 and regulate SHH expression. (d) FGF signaling maintains SHH expression. Abbreviations: SHH, Sonic hedgehog; GLI1-3, glioma-associated oncogene homolog; PTCH1, Patched1; SMO, Smoothened; SUFU, Suppressor of fused homolog; KIF7, Kinesin family member 7; TSG, Twisted gastrulation; CHD, Chordin; NOG, Noggin; BMP, Bone morphogenic protein; P, Phosphate; SMAD, Mothers against decapentaplegic homolog; NODAL, Nodal growth differentiation factor; ZIC2, Zinc finger protein 2; SIX3, SIX homeobox 3; FGF/FGFR1, Fibroblast growth factor/receptor 1.

Figure 4

Lissencephaly manifests with a reduction in the normal brain folds. (a) A schematic of a lissencephalic and a normal brain. (b–d) Mutations in LIS1 result in a more severe phenotype in the caudal part of the brain (b), whereas mutations in DCX affect more the rostral part of the brain (c), as shown in comparison with the normal brain (d).