Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

Abstract

Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisions, differentiation and migration of these committed CNS progenitors are controlled by the gene regulatory networks that are regulated by various homeodomain-containing transcription factors, including but not limited to those of the Pax (paired), Nkx, Otx (orthodenticle), Gsx/Gsh (genetic screened), and Dlx (distal-less) homeobox gene families. This comprehensive review outlines the integral role of key homeobox transcription factors and their target genes on forebrain development, focused primarily on the telencephalon. Furthermore, links of these transcription factors to human diseases, such as neurodevelopmental disorders and brain tumors are provided.

Keywords: DNA binding domain; bHLH factor; development; forebrain; forkhead (Fkh) transcription factors; homeobox.

FIGURE 1

Expression of homeobox genes in the developing embryonic mouse forebrain. (A) Schematic illustration of coronal section of E13.5 forebrain depicting ventricular zone (VZ), subventricular zone (SVZ), and mantle zone (MZ) on the left-hand side and neocortex (NCx), lateral ganglionic eminence (LGE), and medial ganglionic eminence (MGE) on the right-hand side. The VZ and SVZ are the proliferative zones, comprised of progenitor cells. Depending on the identity of these differentiated cells, the cells migrate either tangentially (red arrows) or radially (purple arrows) into the MZ and proceed to mature (Left-hand side). Migration toward the olfactory bulb from the VZ of the LGE also occurs (Right-hand side). (B) 3-dimensional schematic of the developing forebrain. The LGE and MGE are contained within the cortex, above the olfactory bulbs (OB). The midbrain (MB) and hindbrain (HB) are also labeled. Insets show schematic representations of 4 coronal sections taken from the forebrain depicting the expression of key homeobox gene expression patterns from rostral to caudal at embryonic time point E13.5. Gene name colors correspond to the expression color shown in the section. Transcription factor expression can be overlapping or structurally distinct and is related to the function of the individual transcription factor (Allen Institute for Brain Science, 2019). Arx and Meis2, to an extent, are expressed throughout the forebrain, whereas Lhx2, Emx1/2, Pax6, Otx1, and Pou3f2 are expressed in the neocortex and pallium. Dlx1/2, Gsx1, Otx2, and Cux1 are expressed in the GE, Gsx2 is expressed specifically in the LGE, and Nkx2.1, Cux2, Lhx6, and Lhx8 in the MGE. Irx3 is not depicted here as it is expressed in the thalamus (not shown). For detailed depictions of gene expression patterns, readers are encouraged to review the cited primary references or the Allen Brain Atlas: Developing Mouse Brain (Allen Institute for Brain Science, 2019). NCx, neocortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; V, ventricle; VZ, ventricular zone; SVZ, subventricular zone; MZ, mantle zone.

FIGURE 2

Homeobox transcription factors and their key functional domains. (A) Schematic depiction of the domain structure of selected homeobox, bHLH and forkhead transcription factors illustrating the highly conserved nature of the homeodomains and other DNA-binding domains of these transcription factors. Other significant functional domains are also shown. DLX2, but not DLX1, contains a polyhistidine motif in its C-terminus. PAX6 contains both a paired domain, as well as the HD. ARX, along with a HD, also contains a polyalanine repeat and an Aristaless domain. a.a., amino acid. (B) The DNA binding sites for Homeobox, bHLH and Forkhead transcription factors from (A). A consensus DNA binding motif for DLX1 and EMX1 is not available.