Untangling the cortex: Advances in understanding specification and differentiation of corticospinal motor neurons

Abstract

The mature cerebral cortex contains a staggering variety of projection neuron subtypes, and a number of complementary studies have recently begun to define their identity and embryonic origin. Among the different types of cortical projection neurons, subcerebral projection neurons, including corticospinal motor neurons (CSMN), have been extensively studied and some of the molecular controls over their differentiation have been elucidated. Here, we first provide an overview of the approaches used to purify and molecularly profile neuronal populations of the neocortex and, more broadly, of the central nervous system (CNS). Next, we specifically review recent progress in understanding the genes that define and control development of the CSMN population. Finally, we briefly discuss the relevance of this work to current questions regarding the mechanisms of the establishment of projection neuron subtype identity in the neocortex and its implications to direct the differentiation of CSMN for therapeutic benefit.

Figure 1

Plates illustrating dissections of the human brain, spinal cord and nerves from Anatomia del corpo humano by Juan Valverde de Amusco (1560).⁽¹⁾

Figure 2

Spatial and temporal aspects of development of the laminar cortex. A: Schematic representation of the region of interest (boxed). B: In the dorsal telencephalon, neural progenitors in the VZ and later in the SVZ, give rise to PN, which migrate to their appropriate layers. PN subtypes are born in a temporally distinct manner, with the deeper layer neurons born early in development, and the upper layer neurons born later. Each cortical layer contains multiple types of PN that connect to different intracortical, subcortical, and subcerebral targets. CP, cortical plate; Ctx, cortex; IZ, intermediate zone; LGE, lateral ganglionic eminence; LV, lateral ventricle; MGE, medial ganglionic eminence; MZ, marginal zone; PP, preplate; SP, subplate; SVZ, subventricular zone; VZ, ventricular zone; WM, white matter.

Figure 3

Expression of selected PN genes in the embryonic and postnatal mouse brain. Boxed regions illustrate the area for which gene expression is described at A: E15 and B: P14. Asterisks describe relative expression levels, while colored triangles indicate gene expression in specific PN subtypes (where known). For more detailed information on the neuron subtype-specific expression of these genes, we refer to the text, as well as to the following references: Fezf2,^(,–71,74) Ctip2,⁽⁴¹⁾ Sox5,^(41,72,73) Clim1,^(41,93,94) Bhlhb5,^(85,95,96) Otx1,^(78,97) Satb2,^(66,68) Cux1 and Cux2,^(98,99) Tbr1,^(–104) S100a10,⁽⁴¹⁾ Crim1,⁽⁴¹⁾ Diap3,⁽⁴¹⁾ Crym (Mu-Crystallin),⁽⁴¹⁾ Er81.^(102,105) CC, corpus callosum; CP, cortical plate; Ctx, cortex; IZ, intermediate zone; LGE, lateral ganglionic eminence; LV, lateral ventricle; MGE, medial ganglionic eminence; MZ, marginal zone; SP, subplate; Str, striatum; SVZ, subventricular zone; VZ, ventricular zone; WM, white matter.