Fate of Midbrain Dopaminergic Neurons Controlled by the Engrailed Genes

Deficiencies in neurotransmitter-specific cell groups in the midbrain result in prominent neural disorders, including Parkinson's disease, which is caused by the loss of dopaminergic neurons of the substantia nigra. We have investigated in mice the role of the engrailed homeodomain transcription factors, En-1 and En-2, in controlling the developmental fate of midbrain dopaminergic neurons.En-1 is highly expressed by essentially all dopaminergic neurons in the substantia nigra and ventral tegmentum, whereasEn-2 is highly expressed by a subset of them. These neurons are generated and differentiate their dopaminergic phenotype inEn-1/En-2 double null mutants, but disappear soon thereafter. Use of an En-1/tau-LacZknock-in mouse as an autonomous marker for these neurons indicates that they are lost, rather than that they change their neurotransmitter phenotype. A single allele of En-1 on anEn-2 null background is sufficient to produce a wild type-like substantia nigra and ventral tegmentum, whereas in contrast a single allele of En-2 on an En-1 null background results in the survival of only a small proportion of these dopaminergic neurons, a finding that relates to the differential expression of En-1 and En-2. Additional findings indicate that En-1 and En-2 regulate expression of α-synuclein, a gene that is genetically linked to Parkinson's disease. These findings show that the engrailed genes are expressed by midbrain dopaminergic neurons from their generation to adulthood but are not required for their specification. However, the engrailed genes control the survival of midbrain dopaminergic neurons in a gene dose-dependent manner. Our findings also suggest a link between engrailed and Parkinson's disease.

• Publication year

  2001

• Venue

  Journal of Neuroscience

• Publication date

  2001-05-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1523/JNEUROSCI.21-09-03126.2001PMID 11312297PMCID PMC6762576
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders.

  2000cited by this paper
• Engrailed-1 and netrin-1 regulate axon pathfinding by association interneurons that project to motor neurons.

  1999influential reference
• Nurr1, an orphan nuclear receptor, is a transcriptional activator of endogenous tyrosine hydroxylase in neural progenitor cells derived from the adult brain.

  1999cited by this paper
• Dopamine biosynthesis is selectively abolished in substantia nigra/ventral tegmental area but not in hypothalamic neurons in mice with targeted disruption of the Nurr1 gene.

  1998cited by this paper
• Drosophila engrailed can substitute for mouse Engrailed1 function in mid-hindbrain, but not limb development.

  1998cited by this paper
• Ala30Pro mutation in the gene encoding alpha-synuclein in Parkinson's disease.

  1998cited by this paper
• FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate.

  1998cited by this paper
• TrnR2, a novel receptor that mediates neurturin and GDNF signaling through Ret.

  1997cited by this paper
• Mutation in the α-Synuclein Gene Identified in Families with Parkinson's Disease

  1997influential reference
• Dopamine neuron agenesis in Nurr1-deficient mice.

  1997cited by this paper
• Cellular and developmental patterns of expression of Ret and glial cell line-derived neurotrophic factor receptor alpha mRNAs

  1997cited by this paper
• Mutation in the alpha-synuclein gene identified in families with Parkinson's disease.

  1997influential reference
• GDNF-induced activation of the ret protein tyrosine kinase is mediated by GDNFR-alpha, a novel receptor for GDNF.

  1996cited by this paper
• Visualizing an olfactory sensory map.

  1996cited by this paper
• Retroviral Misexpression of engrailed Genes in the Chick Optic Tectum Perturbs the Topographic Targeting of Retinal Axons

  1996cited by this paper
• Parkinson's disease: biology and aetiology

  1996cited by this paper
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  1996cited by this paper
• Diversity and Pattern in the Developing Spinal Cord

  1996cited by this paper
• The engrailed and huckebein genes are essential for development of serotonin neurons in the Drosophila CNS.

  1996cited by this paper
• Rostral optic tectum acquires caudal characteristics following ectopic engrailed expression.

  1996cited by this paper
• Pre- and postnatal development of dopaminergic neuron numbers in the male and female mouse midbrain.

  1996cited by this paper
• GDNF–Induced Activation of the Ret Protein Tyrosine Kinase Is Mediated by GDNFR-α, a Novel Receptor for GDNF

  1996influential reference
• Renal and neuronal abnormalities in mice lacking GDNF

  1996influential reference
• Requirement for LIM homeobox gene Isl1 in motor neuron generation reveals a motor neuron-dependent step in interneuron differentiation.

  1996cited by this paper
• A role for gradient en expression in positional specification on the optic tectum.

  1996cited by this paper
• Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain

  1995cited by this paper
• Independent assignment of antero-posterior and dorso-ventral positional values in the developing chick hindbrain.

  1995cited by this paper
• Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo

  1995influential reference
• Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2.

  1995cited by this paper
• Atlas of the Developing Rat Nervous System.

  1995cited by this paper
• Tau-beta-galactosidase, an axon-targeted fusion protein.

  1994cited by this paper
• Developmental expression of the RET protooncogene.

  1994cited by this paper
• Regulation of Pax-3 expression in the dermomyotome and its role in muscle development.

  1994cited by this paper
• Engrailed controls glial/neuronal cell fate decisions at the midline of the central nervous system.

  1994influential reference
• Abnormal embryonic cerebellar development and patterning of postnatal foliation in two mouse Engrailed-2 mutants.

  1994influential reference
• Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret

  1994influential reference
• Regulation of SC1/DM-GRASP during the migration of motor neurons in the chick embryo brain stem.

  1994cited by this paper
• Multiple developmental defects in Engrailed-1 mutant mice: an early mid-hindbrain deletion and patterning defects in forelimbs and sternum.

  1994influential reference
• Midbrain dopaminergic neurons (nuclei A8, A9, and A10): Three‐dimensional reconstruction in the rat

  1993influential reference
• GDNF: a glial cell line-derived neurotrophic factor for midbrain dopaminergic neurons.

  1993cited by this paper
• The midbrain-hindbrain phenotype of Wnt-1-/Wnt-1- mice results from stepwise deletion of engrailed-expressing cells by 9.5 days postcoitum.

  1992cited by this paper
• A biochemical hallmark of apoptosis: Internucleosomal degradation of the genome

  1992cited by this paper
• New insights into the cause of Parkinson's disease

  1992cited by this paper
• Subtle cerebellar phenotype in mice homozygous for a targeted deletion of the En-2 homeobox.

  1991influential reference
• Birth and differentiation of reticular neurons in the chick hindbrain: ontogeny of the first neuronal population.

  1991cited by this paper
• The rat brain synucleins; family of proteins transiently associated with neuronal membrane.

  1991cited by this paper
• Chromosomal localization of the human homeo box-containing genes, EN1 and EN2.

  1989cited by this paper
• Modifying expression of the engrailed gene of Drosophila melanogaster.

  1988cited by this paper
• Expression of an engrailed‐like gene during development of the early embryonic chick nervous system

  1988cited by this paper
• Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal

  1988cited by this paper
• The pre- and postnatal development of the dopaminergic cell groups in the ventral mesencephalon and the dopaminergic innervation of the striatum of the rat.

  1988cited by this paper
• Expression of the homeo box-containing gene En-2 delineates a specific region of the developing mouse brain.

  1988influential reference
• Expression patterns of the homeo box-containing genes En-1 and En-2 and the proto-oncogene int-1 diverge during mouse development.

  1988influential reference
• A gene with sequence similarity to Drosophila engrailed is expressed during the development of the neural tube and vertebrae in the mouse.

  1988cited by this paper
• Relation of target encounter and neuronal death to nerve growth factor responsiveness in the developing mouse trigeminal ganglion

  1984cited by this paper
• Compartments in the abdomen of Drosophila and the role of the engrailed locus.

  1981cited by this paper
• Engrailed: a gene controlling compartment and segment formation in Drosophila.

  1981cited by this paper

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• ClustSIGNAL identifies cell types and subtypes using an adaptive smoothing approach for scalable spatial clustering

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• Building an action circuit with nigrostriatal dopaminergic neurons and striatonigral neurons.

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• BrainSTEM: A multi-resolution fetal brain atlas to assess the fidelity of human midbrain cultures

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• Conserved roles of engrailed: patterning tissues and specifying cell types.

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• Homeoprotein signaling in the developing and adult nervous system.

  2015cites this paper
• Genetic control of midbrain dopaminergic neuron development

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• Translational Strategies to address Parkinson's disease

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