A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration

Yang, Shanzheng; Toledo, Enrique M.; Rosmaninho, Pedro; Peng, Changgeng; Uhlén, Per; Castro, Diogo S.; Arenas, Ernest

doi:10.1038/s42003-018-0080-0

Cited by 13 publications

(12 citation statements)

References 55 publications

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“…In this feedback loop, PITX3 specifically induces transcription of miR-133b, and miR-133b positively regulates dopaminergic neuron numbers in mouse primary midbrain cultures by downregulating PITX3 ( Kim et al, 2007 ). In another example, a negative feedback loop involving the transcription factor ZEB2 and miR-200c was shown to control the expression and function of several key genes of midbrain DA neuron development ( Yang et al, 2018 ; Figure 1 , bottom-right). Among these genes was Nr4a2 , which encodes for a transcription factor required for the generation of midbrain DA neurons.…”

Section: Neuronal Subtype Determination and Functionmentioning

confidence: 99%

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

Zolboot

Zampa

et al. 2021

Front. Mol. Neurosci.

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Characterizing the diverse cell types that make up the nervous system is essential for understanding how the nervous system is structured and ultimately how it functions. The astonishing range of cellular diversity found in the nervous system emerges from a small pool of neural progenitor cells. These progenitors and their neuronal progeny proceed through sequential gene expression programs to produce different cell lineages and acquire distinct cell fates. These gene expression programs must be tightly regulated in order for the cells to achieve and maintain the proper differentiated state, remain functional throughout life, and avoid cell death. Disruption of developmental programs is associated with a wide range of abnormalities in brain structure and function, further indicating that elucidating their contribution to cellular diversity will be key to understanding brain health. A growing body of evidence suggests that tight regulation of developmental genes requires post-transcriptional regulation of the transcriptome by microRNAs (miRNAs). miRNAs are small non-coding RNAs that function by binding to mRNA targets containing complementary sequences and repressing their translation into protein, thereby providing a layer of precise spatial and temporal control over gene expression. Moreover, the expression profiles and targets of miRNAs show great specificity for distinct cell types, brain regions and developmental stages, suggesting that they are an important parameter of cell type identity. Here, we provide an overview of miRNAs that are critically involved in establishing neural cell identities, focusing on how miRNA-mediated regulation of gene expression modulates neural progenitor expansion, cell fate determination, cell migration, neuronal and glial subtype specification, and finally cell maintenance and survival.

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Section: Neuronal Subtype Determination and Functionmentioning

confidence: 99%

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

Zolboot

Zampa

et al. 2021

Front. Mol. Neurosci.

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“…Both floor plate progenitors (ProgFPL and ProgFPM) are characterized by the expression of LMX1A, a transcription factor that specifies mDA neurons and labels the human floor plate ( Figure 1A) (Andersson et al, 2006b;Hebsgaard et al, 2009;Nelander et al, 2009). Additionally, the lateral floor plate progenitor (ProgFPL) is identified by a high expression of the morphogen WNT1, which is required for midbrain and mDA neuron development in mice (McMahon and Bradley, 1990;Thomas and Capecchi, 1990;Danielian and McMahon, 1996;Prakash et al, 2006;Andersson et al, 2013;Yang et al, 2013), and ZEB2, a transcription factor that regulates mDA progenitor proliferation and neurogenesis (Yang et al, 2018). Conversely, the medial floor plate progenitor (ProgFPM) is characterized by low WNT1 expression.…”

Section: Progenitor Cell Types In the Developing Human Midbrainmentioning

confidence: 99%

Midbrain Dopaminergic Neuron Development at the Single Cell Level: In vivo and in Stem Cells

Ásgrímsdóttir

Arenas

2020

Front. Cell Dev. Biol.

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Parkinson's disease (PD) is a progressive neurodegenerative disorder that predominantly affects dopaminergic (DA) neurons of the substantia nigra. Current treatment options for PD are symptomatic and typically involve the replacement of DA neurotransmission by DA drugs, which relieve the patients of some of their motor symptoms. However, by the time of diagnosis, patients have already lost about 70% of their substantia nigra DA neurons and these drugs offer only temporary relief. Therefore, cell replacement therapy has garnered much interest as a potential treatment option for PD. Early studies using human fetal tissue for transplantation in PD patients provided proof of principle for cell replacement therapy, but they also highlighted the ethical and practical difficulties associated with using human fetal tissue as a cell source. In recent years, advancements in stem cell research have made human pluripotent stem cells (hPSCs) an attractive source of material for cell replacement therapy. Studies on how DA neurons are specified and differentiated in the developing mouse midbrain have allowed us to recapitulate many of the positional and temporal cues needed to generate DA neurons in vitro. However, little is known about the developmental programs that govern human DA neuron development. With the advent of single-cell RNA sequencing (scRNA-seq) and bioinformatics, it has become possible to analyze precious human samples with unprecedented detail and extract valuable high-quality information from large data sets. This technology has allowed the systematic classification of cell types present in the human developing midbrain along with their gene expression patterns. By studying human development in such an unbiased manner, we can begin to elucidate human DA neuron development and determine how much it differs from our knowledge of the rodent brain. Importantly, this molecular description of the function of human cells has become and will increasingly be a reference to define, evaluate, and engineer cell types for PD cell replacement therapy and disease modeling.

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“…When overexpressed in human ESCs, ZEB1 does not immediately decrease pluripotency markers OCT4, NANOG, and SOX2, and most cells are negative for the early neuronal marker TUBB3 up until day 25 of differentiation (Jiang et al, 2018). Since it was demonstrated that Zeb2 overexpression decreases Ngn2 expression in embryonic midbrain cells and a dopaminergic cell line (Yang et al, 2018), a negative correlation between these two TFs might account for the observed weak pro-neurogenic effect. Conversely, forward programming by Ezh2 induction results in the formation of electrophysiological active and synapse-forming neurons, which is comparable to the effect of Ngn1-mediated forward programming.…”

Section: Neuronal Forward Programming Factors Beyond the Bhlh Familymentioning

confidence: 97%

Transcription Factor-Based Fate Specification and Forward Programming for Neural Regeneration

Flitsch

Laupman

Brüstle

2020

Front. Cell. Neurosci.

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Traditionally, in vitro generation of donor cells for brain repair has been dominated by the application of extrinsic growth factors and morphogens. Recent advances in cell engineering strategies such as reprogramming of somatic cells into induced pluripotent stem cells and direct cell fate conversion have impressively demonstrated the feasibility to manipulate cell identities by the overexpression of cell fate-determining transcription factors. These strategies are now increasingly implemented for transcription factorguided differentiation of neural precursors and forward programming of pluripotent stem cells toward specific neural subtypes. This review covers major achievements, pros and cons, as well as future prospects of transcription factor-based cell fate specification and the applicability of these approaches for the generation of donor cells for brain repair.

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A Zeb2-miR-200c loop controls midbrain dopaminergic neuron neurogenesis and migration

Cited by 13 publications

References 55 publications

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

Midbrain Dopaminergic Neuron Development at the Single Cell Level: In vivo and in Stem Cells

Transcription Factor-Based Fate Specification and Forward Programming for Neural Regeneration

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