Roles of Transcription Factors in the Development and Reprogramming of the Dopaminergic Neurons

Abstract

The meso-diencephalic dopaminergic (mdDA) neurons regulate various critical processes in the mammalian nervous system, including voluntary movement and a wide range of behaviors such as mood, reward, addiction, and stress. mdDA neuronal loss is linked with one of the most prominent human movement neurological disorders, Parkinson’s disease (PD). How these cells die and regenerate are two of the most hotly debated PD research topics. As for the latter, it has been long known that a series of transcription factors (TFs) involves the development of mdDA neurons, specifying cell types and controlling developmental patterns. In vitro and in vivo, TFs regulate the expression of tyrosine hydroxylase, a dopamine transporter, vesicular monoamine transporter 2, and L-aromatic amino acid decarboxylase, all of which are critical for dopamine synthesis and transport in dopaminergic neurons (DA neurons). In this review, we encapsulate the molecular mechanism of TFs underlying embryonic growth and maturation of mdDA neurons and update achievements on dopaminergic cell therapy dependent on knowledge of TFs in mdDA neuronal development. We believe that a deeper understanding of the extrinsic and intrinsic factors that influence DA neurons’ fate and development in the midbrain could lead to a better strategy for PD cell therapy.

Single-cell transcriptomic atlas of the human substantia nigra in Parkinson’s disease

“…A significant finding from our study is the identification of three molecularly distinct subtypes of DA neurons in human aged SN. The classification of human DA neurons in our study shows clear distinction from that of the previous mouse midbrain DA neurons, which are largely based on the TFs determining the formation and differentiation of DA neurons during mouse brain development 25 . While the three human DA neuron subtypes degenerate in PD, the composition of the rest cell types remains relatively unaltered in the SN.…”

“…Multiple studies have demonstrated the classification of DA neurons in mouse midbrain based on molecular profiling associated with the expression of distinct transcription factors (TF) confined in specific subtypes of DA neurons 16 . By examining the TFs, many of which are critical for DA neuron specification or differentiation during development 25 , we found that the vast majority are expressed in a significantly low fractions of all cell clusters (including the three DA subclusters) in human aged SN from both the control and PD. MYT1L is an exception – it expressed in large fractions in the main neuron clusters ( Fig.…”

Parkinson’s Disease: Overview of Transcription Factor Regulation, Genetics, and Cellular and Animal Models

“…Studies using mouse genetic and in vitro models have demonstrated that the development and maintenance of mDA neurons are delicately regulated by genetic and signaling networks, including several transcription factors (TFs). During the development of mouse mDA neurons, unique sets of TFs are activated, including Engrailed-1/Engrailed-2, Foxa1/2, Lmx1a/b, Nurr1, Otx2, and Pitx3 ( Davidson et al, 1988 ; Law et al, 1992 ; Smidt et al, 1997 , 2000 ; Kittappa et al, 2007 ; Alavian et al, 2008 , 2014 ; Chung et al, 2009 ; Rodriguez-Traver et al, 2016 ; Tian et al, 2022 ). Recent single-cell RNA-seq analysis on developing human brains has confirmed their induction in human mDA neurons as well ( Eze et al, 2021 ).…”

“…Specification of mDA neurons progenitors depends on the interaction of signal molecules [e.g., Sonic Hedgehog (SHH) and wingless-type MMTV integration site family, member 1 (WNT1)], growth factors [e.g., glial cell line-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 8 (FGF8)], and a series of key TFs including En1/2, Otx2, Lmx1a/b, and Foxa1/2 ( Arenas, 2008 ; Simeone et al, 2011 ; Joksimovic and Awatramani, 2014 ; Maury et al, 2015 ; Brodski et al, 2019 ). The subsequent differentiation and maturation of mDA neurons requires the expression of Nurr1 and Pitx3, which control the expression of several marker genes for mature mDA neurons, such as TH (tyrosine hydroxylase), DAT (Dopamine active transporter, encoded by the SLC6A3 gene) and VMAT2 (vesicular monoamine transporter 2), AADC (DOPA decarboxylase), DRD2 (dopamine receptor D2), or ALDH1A1 (aldehyde dehydrogenase 1 family, member A1) ( Tian et al, 2022 ).…”

“…These TFs remain present in adult mDA neurons and are required for long-term survival of mDA neuron ( Alavian et al, 2008 , 2014 ; Tian et al, 2022 ). Importantly, disruption of one of these TFs in mouse genetic models displays several features reminiscent of PD.…”