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.

Molecular diversity and evolution of neuron types in the amniote brain

“…Brain regions and individual nuclei within them (spatially validated by the criteria listed above) are thus identifiable by the combinatorial expression of sets of transcription factors. For example, telencephalic glutamatergic neurons could be distinguished by the coexpression of foxg1 and zbtb18 ( 18 ); thalamic glutamatergic neurons by tcf7l2 and lhx9 ( 19 , 20 ); habenular neurons by tcf7l2 , zic1 , lhx9 , and pou4f1 ( 19 ); cerebellar granule cells and interneurons, but not Purkinje cells, by zic1 , zbtb18 , and nfix ( 21 ); medial ganglionic eminence–derived γ-aminobutyric acid–releasing (GABAergic) neurons by foxg1 , arx , lhx6 , dlx5 , and zeb2 ( 22 ); lateral ganglionic eminence–derived GABAergic neurons by foxg1 , meis2 , and dlx5 ( 23 ); and GABAergic neurons of the tegmentum and tectum express tal1 and gata3 , but mostly tegmental neurons express nr2f2 ( 24 ) (Fig. 1F).…”

Missense mutations in CRX homeodomain cause dominant retinopathies through two distinct mechanisms

“…Hundreds of HD TFs have subsequently been documented in regulating gene expression programs important for body plan specification, pattern formation and cell fate determination 1,2 . Mutations in HD TFs have been linked to many human diseases, including neuropsychiatric and neurodegenerative conditions 3,4 . Although significant progress has been made in understanding HD-DNA interactions, uncovering the pathogenetic mechanisms of disease-causing missense mutations in HD have proven challenging.…”

A simplified protocol for the generation of cortical brain organoids

“…Immunofluorescent characterization shows that such regions contain ventricle-like cavities surrounded by choroid plexus epithelia (TRR + ), as well as GSX2-expressing ventral forebrain progenitor cells (Figure 5B), which are both cell types that derive from the rostral neural tube during early embryonic development (Liddelow, 2015;Leung et al, 2022). Whereas, newborn neurons at early stages can still be dispersed, and more compact and organized bands of neurons will be visible in mature organoids (Figure 6).…”