Gata2, Nkx2-2 and Skor2 form a transcription factor network regulating development of a midbrain GABAergic neuron subtype with characteristics of REM sleep regulatory neurons

The midbrain reticular formation is a mosaic of diverse GABAergic and glutamatergic neurons that have been associated with a variety of functions, including the regulation of sleep. However the molecular characteristics and development of the midbrain reticular formation neurons are poorly understood. As the transcription factor Gata2 is required for the development of all GABAergic neurons derived from the embryonic mouse midbrain, we hypothesized that the genes expressed downstream of Gata2 could contribute to the diversification of GABAergic neuron subtypes in this brain region. Here, we show that Gata2 is indeed required for the expression of several lineage-specific transcription factors in post-mitotic midbrain GABAergic neuron precursors. These include a homeodomain transcription factor Nkx2-2 and a SKI family transcriptional repressor Skor2, which are co-expressed in a restricted group of GABAergic precursors in the midbrain reticular formation. Both Gata2, and Nkx2-2 function is required for the expression of Skor2 in GABAergic precursors. In the adult mouse as well as rat midbrain, the Nkx2-2 and Skor2 expressing GABAergic neurons locate at the boundary of the ventrolateral periaqueductal gray and the midbrain reticular formation, an area shown to contain REM-off neurons regulating REM sleep. In addition to the characteristic localization, the Skor2 positive cells increase their activity upon REM sleep inhibition, send projections to a pontine region associated with sleep control and are responsive to orexins, consistent with the known properties of the midbrain REM-off neurons.

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Extracellular potassium ion activity in the midbrain reticular formation during REM sleep

Neuroscience Letters ◽

10.1016/0304-3940(79)91641-0 ◽

1979 ◽

Vol 11 ◽

pp. 57

Author(s):

Toyohiko Satoh ◽

Naomi Mutsuga

Keyword(s):

Reticular Formation ◽

Rem Sleep ◽

Potassium Ion ◽

Extracellular Potassium ◽

Midbrain Reticular Formation ◽

Ion Activity

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Faculty Opinions recommendation of A nonclassical bHLH Rbpj transcription factor complex is required for specification of GABAergic neurons independent of Notch signaling.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1104439.559703 ◽

2008 ◽

Author(s):

Jean-François Brunet

Keyword(s):

Transcription Factor ◽

Notch Signaling ◽

Gabaergic Neurons ◽

Transcription Factor Complex

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The opiate antagonist naloxone does not consistently block inhibition of spinal nociceptive transmission produced by stimulation in lateral midbrain reticular formation of the cat

Neuroscience Letters ◽

10.1016/0304-3940(80)90170-6 ◽

1980 ◽

Vol 20 (3) ◽

pp. 335-339 ◽

Cited By ~ 6

Author(s):

E. Carstens ◽

M. Zimmermann

Keyword(s):

Reticular Formation ◽

Opiate Antagonist ◽

Nociceptive Transmission ◽

Midbrain Reticular Formation

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Myf5 is a novel early axonal marker in the mouse brain and is subjected to post-transcriptional regulation in neurons

Development ◽

10.1242/dev.127.2.319 ◽

2000 ◽

Vol 127 (2) ◽

pp. 319-331 ◽

Cited By ~ 1

Author(s):

P. Daubas ◽

S. Tajbakhsh ◽

J. Hadchouel ◽

M. Primig ◽

M. Buckingham

Keyword(s):

Transcription Factor ◽

Mouse Brain ◽

Mrna Translation ◽

Adult Brain ◽

Protein Accumulation ◽

Embryonic Mouse ◽

Signalling Molecules ◽

Basic Helix Loop Helix ◽

Helix Loop Helix ◽

The Brain

Myf5 is a key basic Helix-Loop-Helix transcription factor capable of converting many non-muscle cells into muscle. Together with MyoD it is essential for initiating the skeletal muscle programme in the embryo. We previously identified unexpected restricted domains of Myf5 transcription in the embryonic mouse brain, first revealed by Myf5-nlacZ(+/)(−) embryos (Tajbakhsh, S. and Buckingham, M. (1995) Development 121, 4077–4083). We have now further characterized these Myf5 expressing neurons. Retrograde labeling with diI, and the use of a transgenic mouse line expressing lacZ under the control of Myf5 regulatory sequences, show that Myf5 transcription provides a novel axonal marker of the medial longitudinal fasciculus (mlf) and the mammillotegmental tract (mtt), the earliest longitudinal tracts to be established in the embryonic mouse brain. Tracts projecting caudally from the developing olfactory system are also labelled. nlacZ and lacZ expression persist in the adult brain, in a few ventral domains such as the mammillary bodies of the hypothalamus and the interpeduncular nucleus, potentially derived from the embryonic structures where the Myf5 gene is transcribed. To investigate the role of Myf5 in the brain, we monitored Myf5 protein accumulation by immunofluorescence and immunoblotting in neurons transcribing the gene. Although Myf5 was detected in muscle myotomal cells, it was absent in neurons. This would account for the lack of myogenic conversion in brain structures and the absence of a neural phenotype in homozygous null mutants. RT-PCR experiments show that the splicing of Myf5 primary transcripts occurs correctly in neurons, suggesting that the lack of Myf5 protein accumulation is due to regulation at the level of mRNA translation or protein stability. In the embryonic neuroepithelium, Myf5 is transcribed in differentiated neurons after the expression of neural basic Helix-Loop-Helix transcription factors. The signalling molecules Wnt1 and Sonic hedgehog, implicated in the activation of Myf5 in myogenic progenitor cells in the somite, are also produced in the viscinity of the Myf5 expression domain in the mesencephalon. We show that cells expressing Wnt1 can activate neuronal Myf5-nlacZ gene expression in dissected head explants isolated from E9.5 embryos. Furthermore, the gene encoding the basic Helix-Loop-Helix transcription factor mSim1 is expressed in adjacent cells in both the somite and the brain, suggesting that signalling molecules necessary for the activation of mSim1 as well as Myf5 are present at these different sites in the embryo. This phenomenon may be widespread and it remains to be seen how many other potentially potent regulatory genes, in addition to Myf5, when activated do not accumulate protein at inappropriate sites in the embryo.

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Location and quantification of muscarinic receptor subtypes in rat pons: implications for REM sleep generation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1997.273.3.r896 ◽

1997 ◽

Vol 273 (3) ◽

pp. R896-R904 ◽

Cited By ~ 5

Author(s):

H. A. Baghdoyan

Keyword(s):

Muscarinic Receptor ◽

Reticular Formation ◽

Muscarinic Receptors ◽

Rem Sleep ◽

Binding Sites ◽

Reticular Nucleus ◽

Homogeneous Distribution ◽

Receptor Subtypes ◽

Pontine Reticular Formation ◽

Muscarinic Receptor Subtypes

Microinjecting cholinomimetics into the pontine reticular formation produces a state that resembles natural rapid eye movement (REM) sleep. Evocation of this REM sleeplike states is anatomically site dependent within the pons and is mediated by muscarinic receptors. The cellular and molecular mechanisms underlying cholinergic REM sleep generation and muscarinic receptor subtype involvement remain to be specified. This study tested the hypothesis that muscarinic receptor subtypes are differentially distributed within the oral and caudal divisions of rat pontine reticular nucleus. In vitro receptor autoradiography was used to localize and quantify M1, M2, and M3 binding sites in the pontine reticular formation and in pontine brain stem regions known to regulate REM sleep. M1-M3 binding sites were present in some REM sleep-related nuclei, such as dorsal raphe and locus ceruleus. The pontine reticular formation was found to have a homogeneous distribution of M2 binding sites across its rostral to caudal extent, indicating that anatomic specificity of cholinergic REM sleep induction cannot be accounted for by a differential density of muscarinic receptors.

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Identification of some downstream targets of ARX, a transcription factor implicated in the development of GABAergic neurons

Frontiers in Cellular Neuroscience ◽

10.3389/conf.fnins.2010.15.00007 ◽

2010 ◽

Vol 4 ◽

Author(s):

Friocourt G.

Keyword(s):

Transcription Factor ◽

Gabaergic Neurons ◽

Downstream Targets

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ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem

Translational Psychiatry ◽

10.1038/s41398-020-01033-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Francesca Morello ◽

Vootele Voikar ◽

Pihla Parkkinen ◽

Anne Panhelainen ◽

Marko Rosenholm ◽

...

Keyword(s):

Transcription Factor ◽

Dopaminergic Neurons ◽

Dopaminergic System ◽

Developmental Pathways ◽

Neuron Development ◽

Learning Deficits ◽

Glutamatergic Neurons ◽

Midbrain Dopaminergic Neurons ◽

Dopamine Signaling ◽

Neurochemical Changes

Abstract The neural circuits regulating motivation and movement include midbrain dopaminergic neurons and associated inhibitory GABAergic and excitatory glutamatergic neurons in the anterior brainstem. Differentiation of specific subtypes of GABAergic and glutamatergic neurons in the mouse embryonic brainstem is controlled by a transcription factor Tal1. This study characterizes the behavioral and neurochemical changes caused by the absence of Tal1 function. The Tal1cko mutant mice are hyperactive, impulsive, hypersensitive to reward, have learning deficits and a habituation defect in a novel environment. Only minor changes in their dopaminergic system were detected. Amphetamine induced striatal dopamine release and amphetamine induced place preference were normal in Tal1cko mice. Increased dopamine signaling failed to stimulate the locomotor activity of the Tal1cko mice, but instead alleviated their hyperactivity. Altogether, the Tal1cko mice recapitulate many features of the attention and hyperactivity disorders, suggesting a role for Tal1 regulated developmental pathways and neural structures in the control of motivation and movement.

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Midbrain neuronal responses to local and spinal cord temperatures

American Journal of Physiology-Legacy Content ◽

10.1152/ajplegacy.1976.231.5.1573 ◽

1976 ◽

Vol 231 (5) ◽

pp. 1573-1578 ◽

Cited By ~ 27

Author(s):

T Hori ◽

Y Harada

Keyword(s):

Spinal Cord ◽

Firing Rate ◽

Reticular Formation ◽

Single Unit ◽

Neuronal Responses ◽

Heating And Cooling ◽

Midbrain Reticular Formation ◽

Spinal Cord Temperature ◽

Temperature Signal ◽

Cold Sensitive

Water-perfused thermodes were implanted over the lumbothoracic spinal cord and unilaterally in the midbrain of urethan-anesthetized rabbits. Single-unit activities were recorded with steel microelectrodes from the thermosensitive neurons in the midbrain reticular formation (MRF), and the effects of heating and cooling of the spinal cord were studied. Of 38 cold-sensitive MRF neurons studied, 7 units decreased their firing rate upon elevation of spinal cord temperature (Tsc) and 3 units showed the opposite type of response to Tsc. The remaining 28 cold units were not affected by the changes in Tsc between 30 and 43 degrees C. Of 17 warm units, 3 units increased and one unit decreased the firing rate during spinal cord heating. These results suggest that the temperature signal arising from thermosensitive structures in the spinal cord may be transmitted to some of the locally thermosensitive neurons in the MRF.

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