Organization of the human embryonic ventral mesencephalon

Nelander, Jenny; Hebsgaard, Josephine B.; Parmar, Malin

doi:10.1016/j.gep.2009.10.002

Cited by 32 publications

(31 citation statements)

References 20 publications

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“…3A). In rodents, mDA cells appear at E10.5, whereas, in humans, mDA neurogenesis begins between 5.0 and 6.0 weeks post conception (PC), peaks at weeks 6-8 (Almqvist et al, 1996;Nelander et al, 2009) and ceases at weeks 10-11 (Freeman et al, 1991). mDA neurogenesis is controlled by two proneural genes of the basic-helix-loop-helix family, Mash1 (mouse achaete-schute homolog 1) and Ngn2 (Neurog2; neurogenin 2) (Fig.…”

Section: Specification Of Mda Progenitors and Suppression Of Lateral mentioning

confidence: 99%

How to make a midbrain dopaminergic neuron

2015

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Midbrain dopaminergic (mDA) neuron development has been an intense area of research during recent years. This is due in part to a growing interest in regenerative medicine and the hope that treatment for diseases affecting mDA neurons, such as Parkinson's disease (PD), might be facilitated by a better understanding of how these neurons are specified, differentiated and maintained in vivo. This knowledge might help to instruct efforts to generate mDA neurons in vitro, which holds promise not only for cell replacement therapy, but also for disease modeling and drug discovery. In this Primer, we will focus on recent developments in understanding the molecular mechanisms that regulate the development of mDA neurons in vivo, and how they have been used to generate human mDA neurons in vitro from pluripotent stem cells or from somatic cells via direct reprogramming. Current challenges and future avenues in the development of a regenerative medicine for PD will be identified and discussed.

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Section: Specification Of Mda Progenitors and Suppression Of Lateral mentioning

confidence: 99%

How to make a midbrain dopaminergic neuron

2015

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“…2). Whereas Mashl is a general proneural gene, thought to act in a permissive manner (that is, dispensable, not required nor sufficient for DAn generation), Msxl and Ngn2 are essential for the correct development of VM DAn [6,17,18,23,27,[43][44][45][46][47].…”

Section: Expression Of Proneural Genes At Early Differentiation Timesmentioning

confidence: 99%

“…[34]). MASH1 cooperates in a permissive manner in the generation of VM DAn, both in rodents and humans [23,27,46,47]. MSX1 prevents alternative cell fates through the repression of Nl<x6.1 and activates Ngn2 expression [6,24,43,45].…”

Section: Regionalization and Activation Of Developmental Gene Cascadementioning

confidence: 99%

“…VM DAn originate from precursors residing in the mesencephalic floor plate (FP), both in rodents and humans, which show features of radial glia [9][10][11][12], reviewed by [6,[13][14][15][16][17][18][19][20][21][22][23][24]. In spite of the importance of identifying a well-characterized and reliable source of human A9-DAn, the present situation is that all neural stem/precursor cultures explored so far present numerous limitations.…”

Section: Introductionmentioning

confidence: 99%

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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

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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.

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“…In recent years, there are a growing number of online public resources [eg, Allen Brain Atlas (www.brain-map.org); HUDSEN (www.hudsen.org)] providing human brain region specific transcriptome profiling and/or in situ hybridization of the human CNS, which doubtless will advance the field. However, combinatorial gene expression studies with cellular resolution in human at stages when neuronal subtype specification takes place (3-7 weeks) are still very few [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

Detailed Expression Analysis of Regulatory Genes in the Early Developing Human Neural Tube

Marklund

Alekseenko

Andersson

et al. 2014

Stem Cells and Development

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Studies in model organisms constitute the basis of our understanding of the principal molecular mechanisms of cell fate determination in the developing central nervous system. Considering the emergent applications in stem cell-based regenerative medicine, it is important to demonstrate conservation of subtype specific gene expression programs in human as compared to model vertebrates. We have examined the expression patterns of key regulatory genes in neural progenitor cells and their neuronal and glial descendants in the developing human spinal cord, hindbrain, and midbrain, and compared these with developing mouse and chicken embryos. As anticipated, gene expression patterns are highly conserved between these vertebrate species, but there are also features that appear unique to human development. In particular, we find that neither tyrosine hydroxylase nor Nurr1 are specific markers for mesencephalic dopamine neurons, as these genes also are expressed in other neuronal subtypes in the human ventral midbrain and in human embryonic stem cell cultures directed to differentiate towards a ventral mesencephalic identity. Moreover, somatic motor neurons in the ventral spinal cord appear to be produced by two molecularly distinct ventral progenitor populations in the human, raising the possibility that the acquisition of unique ventral progenitor identities may have contributed to the emergence of neural subtypes in higher vertebrates.

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Organization of the human embryonic ventral mesencephalon

Cited by 32 publications

References 20 publications

How to make a midbrain dopaminergic neuron

How to make a midbrain dopaminergic neuron

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

Detailed Expression Analysis of Regulatory Genes in the Early Developing Human Neural Tube

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