A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b

Smidt, Marten P.; Asbreuk, C.H.J; Cox, Joke J.; Chen, Haixu; Johnson, Randy L.; Burbach, J. Peter H.

doi:10.1038/73902

Cited by 363 publications

(355 citation statements)

References 26 publications

Supporting

Mentioning

329

Contrasting

Unclassified

Order By: Relevance

“…Nurr1 is essential for development of the dopaminergic neurotransmitter function in mesencephalic neurons [35]. A second pathway involving Lmx1b and Ptx3 seems to be important for expression of other aspects of the dopaminergic neuronal phenotype [36]. Shh and FGF8 induce the dopaminergic phenotype when present in appropriate concentrations in specific brain regions [33,37,38].…”

Section: Discussionmentioning

confidence: 99%

Dopaminergic Differentiation of Human Embryonic Stem Cells

et al. 2004

View full text Add to dashboard Cite

In this manuscript we report that human embryonic stem cells (hESCs) differentiated into dopaminergic neurons when cocultured with PA6 cells. After 3 weeks of differentiation, approximately 87% of hES colonies contained tyrosine hydroxylase (TH)–positive cells, and a high percentage of the cells in most of the colonies expressed TH. Differentiation was inhibited by exposure to BMP4 or serum. TH‐positive cells derived from hESCs were postmitotic, as determined by bromodeoxyurindine colabeling. Differentiated cells expressed other markers of dopaminergic neurons, including the dopamine transporter, aromatic amino acid decarboxylase, and the transcription factors associated with neuronal and dopaminergic differentiation, Sox1, Nurr1, Ptx3, and Lmx1b. Neurons that had been differentiated on PA6 cells were negative for dopamine‐β‐hydroxylase, a marker of noradrenergic neurons. PA6‐induced neurons were able to release dopamine and 3,4‐dihydroxphe‐hylacetic acid (DOPAC) but not noradrenalin when depolarized by high K+. When transplanted into 6‐hydroxydopamine–treated animals, hES‐derived dopaminergic cells integrated into the rat striatum. Five weeks after transplantation, surviving TH‐positive cells were present but in very small numbers compared with the high frequency of TH‐positive cells seen in PA6 coculture. Larger numbers of cells positive for smooth muscle actin, but no undifferentiated ES cells, were present after transplantation. Therefore, hESCs can be used to generate human dopaminergic cells that exhibit biochemical and functional properties consistent with the expected properties of mature dopaminergic neurons.

show abstract

Section: Discussionmentioning

confidence: 99%

Dopaminergic Differentiation of Human Embryonic Stem Cells

et al. 2004

View full text Add to dashboard Cite

show abstract

“…11,42 Previous psychological evaluation of selfreport questionnaires revealed depression in five out of 10 cases and anxiety symptoms in five out of eight subjects, respectively. 42 In the present psychological assessment of 75 individuals, however, we found no evidence for psychological symptoms such as depression and mood symptoms associated with NPS.…”

Section: Discussionmentioning

confidence: 99%

Genotype–phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy

et al. 2005

View full text Add to dashboard Cite

Nail-patella syndrome (NPS) is characterized by developmental defects of dorsal limb structures, nephropathy, and glaucoma and is caused by heterozygous mutations in the LIM homeodomain transcription factor LMX1B. In order to identify possible genotype-phenotype correlations, we performed LMX1B mutation analysis and comprehensive investigations of limb, renal, ocular, and audiological characteristics in 106 subjects from 32 NPS families. Remarkable phenotypic variability at the individual, intrafamilial, and interfamilial level was observed for different NPS manifestations. Quantitative urinanalysis revealed proteinuria in 21.3% of individuals. Microalbuminuria was detected in 21.7% of subjects without overt proteinuria. Interestingly, nephropathy appeared significantly more frequent in females. A significant association was established between the presence of clinically relevant renal involvement in an NPS patient and a positive family history of nephropathy. We identified normal-tension glaucoma (NTG) and sensorineural hearing impairment as new symptoms associated with NPS. Sequencing of LMX1B revealed 18 different mutations, including six novel variants, in 28 families. Individuals with an LMX1B mutation located in the homeodomain showed significantly more frequent and higher values of proteinuria compared to subjects carrying mutations in the LIM domains. No clear genotype -phenotype association was apparent for extrarenal manifestations. This is the first study indicating that family history of nephropathy and mutation location might be important in precipitating individual risks for developing NPS renal disease. We suggest that the NPS phenotype is broader than previously described and that NTG and hearing impairment are part of NPS. Further studies on modifier factors are needed to understand the mechanisms underlying phenotypic heterogeneity.

show abstract

“…Nurrl expression in the mouse (cooperating with Pitx3) is critical for the acquisition of the correct DA phenotype (that requires co-expression of TH, AADC, VMAT2 and DAT) [17,22,73,74]. In relation to LMX1B, loss of function studies indicate that is required for the maintenance of VM DAn [75], and more recently it has been involved in patterning [12,18,76]. hVMl cells activate NURR1 and LMX1B during the first week of differentiation (Fig.…”

Section: Activation Of Developmental Pro-dopaminergic Genesmentioning

confidence: 99%

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Seiz

Ramos-Gómez

Courtois

et al. 2012

Experimental Cell Research

View full text Add to dashboard Cite

Understanding the molecular programs of the generation of human dopaminergic neurons (DAn) from their ventral mesencephalic (VM) precursors is of key importance for basic studies, progress in cell therapy, drug screening and pharmacology in the context of Parkinson's disease. The nature of human DAn precursors in vitro is poorly understood, their properties unstable, and their availability highly limited. Here we present positive evidence that human VM precursors retaining their genuine properties and long-term capacity to generate A9 type Substantia nigra human DAn (hVMl model cell line) can be propagated in culture. During a one month differentiation, these cells activate all key genes needed to progress from pro-neural and prodopaminergic precursors to mature and functional DAn. For the first time, we demonstrate that gene cascades are correctly activated during differentiation, resulting in the generation of mature DAn. These DAn have morphological and functional properties undistinguishable from those generated by VM primary neuronal cultures. In addition, we have found that the forced expression of Bcl-X L induces an increase in the expression of key developmental genes (MSX1, Abbreviations: A9-DAn, (dopaminergic neuron from the A9 group); 6-OHDA, (6-hidroxydopamine); DA, (dopamine); DAn, (dopaminergic neuron); FB, (forebrain); FP, (floor plate); hESC, (human Embryonic stem cells); hNSC, (human neural stem cells); hVM, (human ventral mesencephalon); SNpc, (substantia nigra pars compacta); TH, (tyrosine hydroxylase); VM, (ventral mesencephalon); VM DAn, (dopaminergic neuron from ventral mesencephalon); VM hNSC, (human neural stem cells from ventral mesencephalon) NGN2), maintenance of PITX3 expression temporal profile, and also enhances genes involved in DAn long-term function, maintenance and survival (ENl, LMXIB, NURRl and PITX3). As a result, Bcl-X L anticipates and enhances DAn generation.

show abstract

A second independent pathway for development of mesencephalic dopaminergic neurons requires Lmx1b

Cited by 363 publications

References 26 publications

Dopaminergic Differentiation of Human Embryonic Stem Cells

Dopaminergic Differentiation of Human Embryonic Stem Cells

Genotype–phenotype studies in nail-patella syndrome show that LMX1B mutation location is involved in the risk of developing nephropathy

Human midbrain precursors activate the expected developmental genetic program and differentiate long-term to functional A9 dopamine neurons in vitro. Enhancement by Bcl-XL

Contact Info

Product

Resources

About