Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development

Maxwell, Sarah; Ho, Hsin‐Yi Henry; Kuehner, Eva; Zhao, Suling; Li, Meng

doi:10.1016/j.ydbio.2005.03.028

Cited by 164 publications

(214 citation statements)

References 37 publications

Supporting

Mentioning

191

Contrasting

Unclassified

Order By: Relevance

“…Normal development of the midbrain central dopaminergic system is controlled by an orchestrated network of transcription factors and morphogens [8][9][10][11][12][13][14]. Besides this network, oxygen signaling emerged as another crucial factor controlling stem cell proliferation and maintenance in various stem and progenitor cell populations, including dopaminergic NPCs [15][16][17].…”

Section: Discussionmentioning

confidence: 99%

“…A distinct network composed of various morphogens [eg, fibroblast growth factor 8, Wnts, and sonic hedghoc (Shh)] and transcription factors (eg, Nurr1, Lmx1a, Pitx3, En1/2, and Ngn2) controls the process of dopaminergic neurogenesis, including the specification and proliferation of dopaminergic NPCs, as well as dopaminergic neurogenesis and maturation and survival of dopaminergic neurons [8][9][10][11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

WagenführLisa

Karen

MarroneLara

et al. 2016

Stem Cells and Development

View full text Add to dashboard Cite

Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen-dependent transcription factor hypoxia-inducible factor 1a (HIF-1a) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1a conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1a signaling. These data-in agreement with in vitro data-indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

WagenführLisa

Karen

MarroneLara

et al. 2016

Stem Cells and Development

View full text Add to dashboard Cite

show abstract

“…These results suggest that FOXA1/2 are not required for regulating DA-specific properties in VTA neurons, perhaps due to a VTA-specific mechanism that is able to compensate for the function of FOXA1/2 deletion in these neurons. It is noteworthy that mutations in other uniformly expressed transcription factors in SNc and VTA neurons have also resulted in defects specific to SNc neurons, suggesting that these neurons are more vulnerable to changes from normal homeostasis (46)(47)(48)(49).…”

Section: Discussionmentioning

confidence: 99%

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Pristerà

Lin

Kaufmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Midbrain dopaminergic (mDA) neurons are implicated in cognitive functions, neuropsychiatric disorders, and pathological conditions; hence understanding genes regulating their homeostasis has medical relevance. Transcription factors FOXA1 and FOXA2 (FOXA1/2) are key determinants of mDA neuronal identity during development, but their roles in adult mDA neurons are unknown. We used a conditional knockout strategy to specifically ablate FOXA1/2 in mDA neurons of adult mice. We show that deletion of Foxa1/2 results in down-regulation of tyrosine hydroxylase, the rate-limiting enzyme of dopamine (DA) biosynthesis, specifically in dopaminergic neurons of the substantia nigra pars compacta (SNc). In addition, DA synthesis and striatal DA transmission were reduced after Foxa1/2 deletion. Furthermore, the burst-firing activity characteristic of SNc mDA neurons was drastically reduced in the absence of FOXA1/2. These molecular and functional alterations lead to a severe feeding deficit in adult Foxa1/2 mutant mice, independently of motor control, which could be rescued by L-DOPA treatment. FOXA1/2 therefore control the maintenance of molecular and physiological properties of SNc mDA neurons and impact on feeding behavior in adult mice.FOXA1 | FOXA2 | dopamine | burst firing | feeding M ost dopaminergic (DAergic) neurons in the adult midbrain are grouped in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). VTA and SNc neurons have been classically linked to diverse functions and different projection targets (1). VTA neurons project to the ventral striatum, cortical areas, and limbic structures. Midbrain dopaminergic (mDA) neurons in this group are implicated in emotional behavior, motivational functions, and reward mechanisms (2-4). On the other hand, SNc neurons mainly project to the dorsal striatum and regulate motor function (5). mDA neurons are of major interest in biomedical research because degeneration of SNc mDA neurons is the hallmark of Parkinson's disease (6). In addition, mDA neuron dysfunction is associated with cognitive impairment, motivational deficits, addiction, and drug abuse (7-10). The identification of factors that maintain dopamine (DA) function in developed adult neurons may contribute to the understanding of the mechanisms supporting the homeostasis of mDA neurons and therefore help in identifying therapeutic targets to treat disorders arising from dysfunctional mDA neurons.FOXA1 and FOXA2 (FOXA1/2) are members of the wingedhelix/forkhead transcription factors, which share over 95% homology between mice and humans (11). FOXA1/2 are so-called "pioneer proteins" that, by binding to tightly condensed chromatin in promoters and enhancer regions, facilitate access of other transcription factors (12, 13). FOXA1/2 regulate the development of diverse organs, including the lung, liver, pancreas, prostate, and kidneys (14). We have also found that FOXA1/2 play a crucial role in the generation of mDA neurons during early and late development, regulating both their specification and dif...

show abstract

“…Examination of intrinsic transcriptional regulators and extrinsic niche factors critical for mDA development in ESC differentiation has proved to be a powerful means for illuminating or validating their functions in dopaminergic neuron fate specification (6,(16)(17)(18)(19)(20). Notably, engineered expression of mDA transcription factors such as Lmx1a and Pitx3 induced midbrain regional character in derived dopamine neurons (6,19).…”

Section: Dmrt5 Regulates Ventral Mesencephalic Gene Expression In Naïvementioning

confidence: 99%

Doublesex and mab-3–related transcription factor 5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral-medial progenitor fate

Gennet

Gale

Nan

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Understanding the control of cell-fate choices during embryonic stem cell (ESC) differentiation is crucial for harnessing strategies for efficient production of desired cell types for pharmaceutical drug screening and cell transplantation. Here we report the identification of the zinc finger-like doublesex and mab-3-related transcription factor 5 (Dmrt5) as a marker for mammalian ventralmedial mesencephalic neuroepithelium that give rise to dopamine neurons. Gain-and loss-of-function studies in ESC demonstrate that Dmrt5 is critically involved in the specification of ventralmedial neural progenitor cell fate and the subsequent generation of dopamine neurons expressing essential midbrain characteristics. Genome-wide analysis of Dmrt5-mediated transcriptome changes and expression profiling of ventral-medial and ventral-lateral mesencephalic neuroepithelium revealed suppressive and inductive regulatory roles for Dmrt5 in the transcription program associated with the ventral-medial neural progenitor fates. Together, these data identify Dmrt5 as an important player in ventral mesencephalic neural fate specification.A major goal of embryonic stem cell (ESC) research is to direct the cells' differentiation toward specific cell types, especially those targeted by devastating degenerative diseases. The advent of induced pluripotent stem cell technology, with its promise for disease modeling, drug screening, and cell therapy, places further demand on a better understanding on the control of lineage/cell-fate specification from pluripotent stem cells. One neuronal cell type in particular, the midbrain dopaminergic (mDA) neuron, is a prime target in applied stem cell research because of its association with Parkinson's disease.The mDA neurons are generated in the floor plate (FP) region of the ventral midbrain and are uniquely identified by their coexpression of tyrosine hydroxylase (TH) with the mDA-specific homeobox protein Pitx3 (1, 2). During development, local inductive signals-Shh, FGF8, and Wnt1-induce distinct cell-fate potentials through initiation of transcriptional cascades that govern the subsequent differentiation, migration, and maturation of the ventral-most progenitors into mDA neurons (3-5). The distinct cell-fate potentials of ventral midbrain progenitors are defined by domain-identifiable expression of transcription factors. For example, the Lmx1a + Foxa2 + FP exclusively gives rise to mDA neurons, whereas the ventral-lateral domains marked by Meis2, Mab21l2, Helt, and Lhx1 produce glutamatergic or GABAergic neurons (6-9). Perturbation of such a transcription "code" seen in genetic studies often led to misspecification of progenitor identity and subsequently to neural transmitter phenotypes (10-12). These studies demonstrate the mechanism of cell-fate determination to be a balance of the activation of "specification" programs and the repression of alternative fates, as observed in the spinal cord (13). However, how transcription factors coordinate distinct fate choice in the ventral midbrain remains poorl...

show abstract

Pitx3 regulates tyrosine hydroxylase expression in the substantia nigra and identifies a subgroup of mesencephalic dopaminergic progenitor neurons during mouse development

Cited by 164 publications

References 37 publications

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice

Doublesex and mab-3–related transcription factor 5 promotes midbrain dopaminergic identity in pluripotent stem cells by enforcing a ventral-medial progenitor fate

Contact Info

Product

Resources

About