Ascl1/Mash1 is required for the development of central serotonergic neurons

Pattyn, Alexandre; Simplicio, Nicolas; Doorninck, J. Hikke van; Goridis, Christo; Guillemot, François; Brunet, Jean‐François

doi:10.1038/nn1247

Cited by 178 publications

(195 citation statements)

References 42 publications

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“…The absence of the BLA and LA in neuroD2-null mice is reminiscent of the absence of specific neuronal populations in mice that lack neurogenin, neurogenin2, math1, mash1, and neuroD (34)(35)(36)(37)(38)(39)(40)(41)(42)(43). Little is known about the reasons that certain populations of neurons are formed but others are absent in mice that are nullizygous for certain neurogenic bHLH factors.…”

Section: Discussionmentioning

confidence: 99%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

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

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The amygdala is centrally involved in formation of emotional memory and response to fear or risk. We have demonstrated that the lateral and basolateral amygdala nuclei fail to form in neuroD2 null mice and neuroD2 heterozygotes have fewer neurons in this region. NeuroD2 heterozygous mice show profound deficits in emotional learning as assessed by fear conditioning. Unconditioned fear was also diminished in neuroD2 heterozygotes compared to wild-type controls. Several key molecular regulators of emotional learning were diminished in the brains of neuroD2 heterozygotes including Ulip1, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor, and GABA A receptor. Thus, neuroD2 is essential for amygdala development and genes involved in amygdala function are altered in neuroD2-deficient mice.basic helix-loop-helix ͉ haploinsufficiency T he amygdala is an almond-shaped brain structure that integrates emotional learning and other emotional responses such as fear perception. The role of the amygdala in fear perception and response was established through lesioning studies in animals and confirmed through positron emission tomography and functional magnetic resonance imaging in normal human subjects and in schizophrenic patients with deficits in fear processing (1-9).We previously reported that neuroD2-null mice on a mixed genetic background are indistinguishable from littermates at birth, but fail to thrive and die within weeks of birth. Before death, nullizygous mice develop ataxia, seizures, cerebellar degeneration, and growth retardation. NeuroD2 heterozygotes appear normal as adults, but have reduced seizure threshold and mild ataxia. We observed aggressive behavior between neuroD2 heterozygotes, which prompted us to evaluate the function and structure of the amygdala and related limbic system brain regions that control aggression, fear, and other emotions. Unconditioned fear (also referred to as anxiety or risk perception) is the response to environmental cues that signal danger. The basolateral amygdala and ventral subiculum of hippocampus are involved in unconditioned fear responses; however, the neuronal circuitry and molecular mechanisms are poorly understood (10).In contrast to unconditioned fear, the neurochemical and molecular basis of emotional learning related to conditioned fear are being elucidated through studies that evaluate fear conditioning in the context of pharmacologic or genetic manipulation of neurotransmitter receptors and second messengers. Fear conditioning involves coupling a neutral conditioned stimulus (CS) such as an audible tone with a noxious unconditioned stimulus (US) such as foot shock and observing that after training and rest periods, that the CS alone is sufficient to elicit behavioral (e.g., freezing) and autonomic responses (11,12). During the training and rest period, the lateral amygdala acquires and consolidates short-and long-term memory that associates the conditioned and unconditioned stimuli through a process known as emotional learning.The acquisition phas...

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Section: Discussionmentioning

confidence: 99%

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Lin

Hansen

Wang

et al. 2005

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

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“…As previously described (15,33), Ngn2 expression extends rostrally into the developing diencephalon where it is expressed outside the zone of dopaminergic neurogenesis. Mash1, another bHLH transcription factor of the proneural family, displays an expression pattern complementary to Ngn2 in the forebrain and has recently been shown to be necessary for the development of brainstem serotonergic neurons (26). The Mash1-expressing cells were distributed both caudal to the MHB, corresponding to the location of the newly-formed 5HT-positive neurons (Fig.…”

Section: Ngn2 Is Specific For the Da Neuron Domain Of The Ventral Midmentioning

confidence: 92%

Neurogenin2 identifies a transplantable dopamine neuron precursor in the developing ventral mesencephalon

Thompson

Andersson

Jensen

et al. 2006

Experimental Neurology

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“…6 E and F) remained largely normal in the mot mutant. zash1a encodes a basic helix-loop-helix transcription regulator (11) and is the zebrafish homologue of mammalian mash1, which is important for the development of central NA and 5HT neurons (12). lim1 encodes a LIM homeodomain (HD) transcription regulator (13) and is expressed in the forebrain and hindbrain progenitor cells that are in close proximity to forebrain and hindbrain MA neurons.…”

Section: Overexpression Of Mot͞med12 Leads To Premature Differentiationmentioning

confidence: 99%

A subunit of the mediator complex regulates vertebrate neuronal development

Wang

Yang

Uno

et al. 2006

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

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The unique profiles of gene expression dictate distinct cellular identity. How these profiles are established during development is not clear. Here we report that the mutant motionless (mot), identified in a genetic screen for mutations that affect neuronal development in zebrafish, displays deficits of monoaminergic neurons and cranial sensory ganglia, whereas expression of the panneuronal marker Hu is largely unperturbed; GABAergic and subsets of cranial motor neurons do not appear to be deficient. Positional cloning reveals that mot encodes Med12, a component of the evolutionarily conserved Mediator complex, whose in vivo function is not well understood in vertebrates. mot͞med12 transcripts are enriched in the embryonic brain and appear distinct from two other Mediator components Med17 and Med21. Delivery of human med12 RNA into zebrafish restores normality to the mot mutant and, strikingly, leads to premature neuronal differentiation and an increased production of monoaminergic neuronal subtypes in WT. Further investigation reveals that mot͞med12 is necessary to regulate, and when overexpressed is capable of increasing, the expression of distinct neuronal determination genes, including zash1a and lim1, and serves as an in vivo cofactor for Sox9 in this process. Together, our analyses reveal a regulatory role of Mot͞ Med12 in vertebrate neuronal development. D uring vertebrate development, pluripotent stem cells respond to spatially localized signals that regulate their cell cycle exit and subsequent differentiation into specialized cell types. The central nervous system contains a large number of different cell types and has been an organ of interest for studying progenitor cell commitment͞differentiation and the generation of cellular diversity (1, 2). In addition to spatial control, temporal regulation of neuronal development has been appreciated but is much less understood in the vertebrate nervous system (3, 4). It is widely accepted that progenitor cells need to establish unique profiles of gene expression that dictate their final destiny. Intracellular pathways underlying the establishment of precise gene expression patterns in the developing nervous system are not well understood.We have undertaken a genetic approach to characterize genes and pathways that control vertebrate neuronal development by using zebrafish as a model system (5-8). Here, we describe the molecular characterization of the motionless (mot) mutant isolated from our genetic screen. The mot mutant embryos have defects in movement and neuronal and cardiovascular development (9). Current analyses reveal that they have normal brain patterning and do not suffer a global deficit of neurons as evidenced by largely unperturbed expression of the pan-neuronal marker Hu. However, the mot mutant exhibits deficits in neuronal subtypes that include monoaminergic (MA) neurons [forebrain dopaminergic and serotonergic (5HT) neurons, hindbrain noradrenergic (NA) and 5HT neurons, and neural-crest derived sympathetic neurons] and cranial sensory gangli...

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Ascl1/Mash1 is required for the development of central serotonergic neurons

Cited by 178 publications

References 42 publications

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

The dosage of the neuroD2 transcription factor regulates amygdala development and emotional learning

Neurogenin2 identifies a transplantable dopamine neuron precursor in the developing ventral mesencephalon

A subunit of the mediator complex regulates vertebrate neuronal development

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