Midbrain dopaminergic neurons: control of their cell fate by the engrailed transcription factors

Abstract

As for any other cell population, the development, cell fate, and properties of mesencephalic dopaminergic (mesDA) neurons are ultimately controlled at the transcriptional level. The genes for two transcription factors Engrailed-1 ( En1) and Engrailed-2 ( En2) play an essential role in the development and maintenance of these cells. They belong to a family of genes that have been investigated in Drosophila for more than half a century. The products of these genes are all characterized by homeotic tissue transformation and a highly conserved protein sequence, the homeobox. En1 and En2 act upon at least two steps of the differentiation of mesDA neurons. They take part in the regionalization event, which gives rise to the neuroepithelium that provides the precursor cells in the ventral midbrain with the fibroblast growth factor 8 signal necessary for their induction. Additionally, these genes are required in postmitotic mesDA neurons in which they are expressed from embryonic day 12 continuously into adulthood. In mutant mice homozygous null for En1 and En2, the neurons are generated in the ventral midbrain, become postmitotic, and begin to express their neurotransmitter phenotype. However, thereafter, they rapidly die by apoptosis. Cell mixing experiments in vitro and in vivo have demonstrated that the engrailed requirement for the survival of mesDA neurons is cell-autonomous. The inactivation of engrailed by RNA interference induces apoptosis in less than 24 h. These data suggest that the engrailed genes control an essential mechanism for the survival of mesDA neurons.

Dopaminergic Differentiation of Human Embryonic Stem Cells

“…Dopaminergic neurons in general express particular and unique patterns of proteins and mRNA molecules. Among these markers are several unique transcription and differentiation factors, some of which promote the development of region-specific subtypes of dopaminergic neurons [30]. Consistent with this notion, the tyrosine hydroxylase promoter contains elements that are specifically activated in different brain regions [31].…”

“…Nurr1, Lmx1b, and Ptx3 transcription factors are mesencephalon specific, whereas the messenger molecules Shh and FGF8 seem to promote the dopaminergic phenotype irrespective of brain region [30,32,33]. Other transcription factors, including Sox1, influence neuronal specification per se [34].…”

Advances in behavioral genetics: mouse models of autism

“…9,11,138 Similar to the HOX genes, EN2 encodes a transcription factor important for neurodevelopment, with a critical role in the formation of specific serotonergic and noradrenergic mid-and hindbrain nuclei, 295 and in the survival of specific dopaminergic subpopulations. [296][297][298] En2 deletion animals have behavioral and neuroanatomical abnormalities that reflect alterations in autism. 15,299 For example, both juvenile and adult En2-null mice show deficits in social interaction.…”

Interaction of the LMX1B and PAX2 gene products suggests possible molecular basis of differential phenotypes in Nail–Patella syndrome

“…Coexpression has also been described in the central nervous system during dopaminergic and GABAergic neuronal differentiation. 14,15 We used the yeast two-hybrid assay also to map the interaction domain of LMX1B: two deletion constructs (Figure 1b), the first including LIM-A and LIM-B domains and lacking the homeodomain, the second lacking the N-terminal half of the coding region, and therefore including the homeodomain and lacking LIM-A and LIM-B domains.…”