The Basic Helix-Loop-Helix Gene Nato3 Drives Expression of Dopaminergic Neuron Transcription Factors in Neural Progenitors

Peterson, Doug J.; Marckini, Darcy N.; Straight, Jordan; King, Elizabeth; Johnson, Wendell; Sarah, Sarala; Chowdhary, Puneet K.; DeLano-Taylor, Merritt

doi:10.1016/j.neuroscience.2019.09.003

Cited by 6 publications

(7 citation statements)

References 54 publications

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“…Nato3 is classically known as a neurogenic transcription factor, expressed in the floor plate cells in the developing mesencephalon and spinal cord32,34 . Although Nato3 expression in the spinal cord of postnatal and adult mice has been reported59 , we found here its presence Foxa2 and thereby indirectly regulates the late transcription factor Nurr133,51 . Since Lmx1b, Foxa2 and Nurr1 are neuroprotective transcription factors9,12,13,19 , Nato3 might contribute to dopaminergic neuroprotection by regulating these genes.…”

contrasting

confidence: 48%

“…Interestingly, it has been shown that Nato3 is expressed in the progenitors of mDA neurons and is required for dopaminergic neurogenesis, analogously to the role of Fer2 in the genesis of DA neurons in flies 32,33,51 . Furthermore, RNA-seq data from the Genotype-Tissue Expression (GTEx) project (the GTEx Consortium, Nat Genetics, 2013) indicate that, among human tissues, Nato3 expression is relatively restricted to the SN of the adult brain ( Fig.…”

Section: Conditional Deletion Of Nato3 In Differentiated Da Neurons Lmentioning

confidence: 93%

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Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

Miozzo

Stickely

Tas

et al. 2020

Preprint

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The degeneration of dopaminergic (DA) neurons in the substantia nigra is a hallmark of Parkinson’s Disease (PD). Dysregulation of developmental transcription factors is implicated in dopaminergic neurodegeneration, but the underlying molecular mechanisms remain largely unknown. Drosophila Fer2 is a prime example of a developmental transcription factor required for the birth and maintenance of midbrain DA neurons. Using an approach combining ChIP-seq, RNA-seq, and genetic epistasis experiments with PD-linked genes, here we demonstrate that Fer2 controls a transcriptional network to maintain mitochondrial structure and function, and thus confers dopaminergic neuroprotection against genetic and oxidative insults. We further show that conditional ablation of Nato3, a mouse homolog of Fer2, in differentiated DA neurons results in locomotor impairments and mitochondrial abnormality in aged mice. Our results reveal the essential and conserved role of Fer2 homologs in the mitochondrial maintenance of midbrain DA neurons, opening new perspectives for modelling and treating PD.

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confidence: 48%

Section: Conditional Deletion Of Nato3 In Differentiated Da Neurons Lmentioning

confidence: 93%

Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

Miozzo

Stickely

Tas

et al. 2020

Preprint

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“…bHLH proteins, in general, have been shown to be important in neuronal differentiation and proliferation throughout the embryo and specifically in the brain [58][59][60][61]. Recently, other bHLH proteins have been identified to be involved in FP patterning, expansion of the progenitor pool, and mdDA neurogenesis during embryogenesis [62][63][64][65]. The bHLH protein Nato3 is expressed in the FP throughout development and has been shown to be involved in the regulation of multiple genes involved in mdDA neurogenesis and mdDA neuron lineage commitment [62,64].…”

Section: Fp Patterning In the Midbrainmentioning

confidence: 99%

“…Recently, other bHLH proteins have been identified to be involved in FP patterning, expansion of the progenitor pool, and mdDA neurogenesis during embryogenesis [62][63][64][65]. The bHLH protein Nato3 is expressed in the FP throughout development and has been shown to be involved in the regulation of multiple genes involved in mdDA neurogenesis and mdDA neuron lineage commitment [62,64]. Loss of Nato3 in the FP leads to a decrease in mdDA neurons, suggesting that it could be importantly involved in expansion of the progenitor pool in the murine FP [62].…”

Section: Fp Patterning In the Midbrainmentioning

confidence: 99%

Acquisition of the Midbrain Dopaminergic Neuronal Identity

Mesman

Smidt

2020

IJMS

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The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies.

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“…The function of bHLH proteins differs throughout embryonic development and is dependent on their spatial-temporal expression pattern and binding partner(s) [12,13]. Several members of the bHLH protein family, e.g., Ascl1 (Mash1), Ngn2, Tcf12, and Nato3, have been shown to be involved in early stages of mdDA neuronal development during fate decision of neural progenitors and later subset specification [14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

2021

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During development, mesodiencephalic dopaminergic (mdDA) neurons form into different molecular subsets. Knowledge of which factors contribute to the specification of these subsets is currently insufficient. In this study, we examined the role of Tcf4, a member of the E-box protein family, in mdDA neuronal development and subset specification. We show that Tcf4 is expressed throughout development, but is no longer detected in adult midbrain. Deletion of Tcf4 results in an initial increase in TH-expressing neurons at E11.5, but this normalizes at later embryonic stages. However, the caudal subset marker Nxph3 and rostral subset marker Ahd2 are affected at E14.5, indicating that Tcf4 is involved in correct differentiation of mdDA neuronal subsets. At P0, expression of these markers partially recovers, whereas expression of Th transcript and TH protein appears to be affected in lateral parts of the mdDA neuronal population. The initial increase in TH-expressing cells and delay in subset specification could be due to the increase in expression of the bHLH factor Ascl1, known for its role in mdDA neuronal differentiation, upon loss of Tcf4. Taken together, our data identified a minor role for Tcf4 in mdDA neuronal development and subset specification.

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The Basic Helix-Loop-Helix Gene Nato3 Drives Expression of Dopaminergic Neuron Transcription Factors in Neural Progenitors

Cited by 6 publications

References 54 publications

Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

Maintenance of mitochondrial integrity in midbrain dopaminergic neurons governed by a conserved developmental transcription factor

Acquisition of the Midbrain Dopaminergic Neuronal Identity

Tcf4 Is Involved in Subset Specification of Mesodiencephalic Dopaminergic Neurons

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