A transcription factor collective defines the HSN serotonergic neuron regulatory landscape

Lloret-Fernández, Carla; Maicas, Miren; Mora‐Martinez, Carlos; Artacho, Alejandro; Jimeno-Martín, Ángela; Chirivella, Laura; Weinberg, Peter J.; Flames, Nuria

doi:10.7554/elife.32785

Cited by 50 publications

(75 citation statements)

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“…Two orthologous POU homeobox genes, C. elegans unc-86 and mouse Brn3a, both act as terminal selectors of neuronal identity. Previous work has shown that unc-86 and Brn3a are required during development to initiate the terminal differentiation program of a number of different neuronal classes [7][8][9][10][11][12][13][15][16][17][18]. In both worms and mice, the terminal gene batteries controlled by these POU homeobox genes are similar and include Figure S3.…”

Section: Discussionmentioning

confidence: 98%

“…The activity of subtype-specific cofactors could also explain the incomplete penetrance of the Brn3a mutant phenotype that we described here. Subtypespecific partnering of mouse Brn3a with other transcription factors is also very reminiscent of C. elegans unc-86, which specifies the identity of related neurons through the interaction with neuron-class-specific cofactors [8,[10][11][12][13]40]. In some of these cases, removal of unc-86 alone shows partially penetrant phenotype, and it is only the joint removal of unc-86 and its cofactor that results in fully penetrant loss-of-identity phenotypes [8,11].…”

Section: Discussionmentioning

confidence: 99%

“…Here, we test this hypothesis by investigating the function of two orthologous POU homeobox genes in nematodes and mice. The C. elegans POU homeobox gene unc-86 is a terminal selector that is required during development to initiate the terminal differentiation program of several distinct neuron classes [4][5][6][7][8][9][10][11][12][13]. Through post-developmental removal of unc-86 activity, we show here that unc-86 is also continuously required throughout the life of many neuron classes to maintain neuron-class-specific identity features.…”

Section: In Briefmentioning

confidence: 99%

“…Neuron Classes in C. elegans POU (Pit1/Oct1/UNC-86) homeobox genes are highly conserved transcription factors with orthologs ranging from nematodes to mammals ( Figures 1A and S1) [22]. One of the founding members of the POU homeobox gene family, the C. elegans unc-86 gene, specifies many identity aspects of more than a dozen different neuron classes during development [4][5][6][7][8][9][10][11][12][13] (summarized in Table S1). For example, unc-86 is required to specify the glutamatergic identity of 4 sensory and interneurons (as measured by the expression of the vesicular glutamate transporter eat-4/VGluT) [8] and the cholinergic identity of 7 sensory, inter-, and motor neurons (as measured by the expression of the acetylcholine synthesizing enzyme and transporters) [9,11].…”

Section: Unc-86 Maintains the Terminal Identity Of Distinctmentioning

confidence: 99%

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BRN3-type POU Homeobox Genes Maintain the Identity of Mature Postmitotic Neurons in Nematodes and Mice

et al. 2018

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Many distinct regulatory factors have been shown to be required for the proper initiation of neuron-type-specific differentiation programs, but much less is known about the regulatory programs that maintain the differentiated state in the adult [1-3]. One possibility is that regulatory factors that initiate a terminal differentiation program during development are continuously required to maintain the differentiated state. Here, we test this hypothesis by investigating the function of two orthologous POU homeobox genes in nematodes and mice. The C. elegans POU homeobox gene unc-86 is a terminal selector that is required during development to initiate the terminal differentiation program of several distinct neuron classes [4-13]. Through post-developmental removal of unc-86 activity, we show here that unc-86 is also continuously required throughout the life of many neuron classes to maintain neuron-class-specific identity features. Similarly, the mouse unc-86 ortholog Brn3a/POU4F1 has been shown to control the initiation of the terminal differentiation program of distinct neuron types across the mouse brain, such as the medial habenular neurons [14-20]. By conditionally removing Brn3a in the adult mouse central nervous system, we show that, like its invertebrate ortholog unc-86, Brn3a is also required for the maintenance of terminal identity features of medial habenular neurons. In addition, Brn3a is required for the survival of these neurons, indicating that identity maintenance and survival are genetically linked. We conclude that the continuous expression of transcription factors is essential for the active maintenance of the differentiated state of a neuron across phylogeny.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: In Briefmentioning

confidence: 99%

Section: Unc-86 Maintains the Terminal Identity Of Distinctmentioning

confidence: 99%

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BRN3-type POU Homeobox Genes Maintain the Identity of Mature Postmitotic Neurons in Nematodes and Mice

et al. 2018

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“…MGE, POa and septum). The role of Er81 in the dopaminergic Hobert, 2009) (Cave et al, 2010) and serotoninergic cell fates (Lloret-Fernandez et al, 2018) and here, in cholinergic cell identity, suggest a general regulatory mechanism of Er81 on the emergence of functional neuromodulatory systems in the developing brain.…”

Section: Control Of the Cholinergic Cell Identitymentioning

confidence: 66%

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

Ranjbar-Slamloo

Ahmed

Abed

et al. 2020

Preprint

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Highlights-The Er81 transcription factor is expressed in striatal cholinergic interneurons (CINs) -Conditional deletion of Er81 alters key molecular, morphological and electrophysiological properties of CINs in adult mice -Deletion of Er81 reduces the intrinsic excitability of CINs by upregulating delayed rectifier and hyperpolarization-activated currents -Deletion of Er81 alters in vivo striatal activity and habit formation SUMMARYThe finely-tuned activity of cholinergic interneurons (CINs) in the striatum is key for motor control, learning, and habit formation. Yet, the molecular mechanisms that determine their unique functional properties remain poorly explored. Using a combination of genetic and biochemical assays, in vitro and in vivo physiological characterisation, we report that selective ablation of the Er81 transcription factor leads to prominent changes in CIN molecular, morphological and electrophysiological features. In particular, the lack of Er81 amplifies intrinsic delayed-rectifier and hyperpolarization-activated currents, which subsequently alters the tonic and phasic activity of CINs. We further demonstrate that these alterations enhance their pause and time-locked responses to sensorimotor inputs in awake mice. Finally, this study reveals an Er81-dependent developmental mechanism in CINs essential for habit formation in adult mice. RESULTS Er81 is expressed in the striatal cholinergic interneuronsWe first analysed the expression of Er81 from birth to adulthood and found that both mRNA ( Figure 1A) and protein levels (Figure 1B) significantly drop from postnatal day 6 (P6) to P30 in the total striatum. In the CINs specifically, we observed similar decrease of Er81 protein levels from P6 to P30 (Figure 1C). To determine the proportion of CINs expressing Er81 at any stage during development, we analysed β-galactosidase staining, which perdures long after being synthesised (Dehorter et al., 2015). We found that most of CINs (62 ± 7 %) in the Er81 nlsLacZ/+ mice express β-galactosidase (and therefore Er81) in the striatum (Figure S1A), unlike cholinergic cells in the basal forebrain (6 ± 2%; Figure S1B). As Er81 can have an important role in cell function (Dehorter et al., 2015), we analysed the consequences of removing Er81 from CINs, using conditional knockout mice (cKO: ChAT-Cre; Er81 f/f ; comparing with control mice: ChAT-Cre; Er81 +/+ ). We did not observe any change in cholinergic cell density at P2 and P30 within the striatum between control and Er81 cKO conditions (Figure 1D-Fsuggesting that the specific deletion of Er81 does not affect CIN neurogenesis and migration. Cholinergic interneuron properties change in the absence of Er81To determine the role of Er81 in CIN specification and maturation, we assessed the molecular properties of these cells following Er81 deletion. The LIM homeodomain transcription factorLhx6 is expressed in about half of striatal CINs (Lozovaya et al., 2018)and is necessary for MGE-derived GABAergic interneuron specification (Liodis et al., 2007) (Fragkouli et al., ...

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Brn3/POU‐IV‐type POU homeobox genes—Paradigmatic regulators of neuronal identity across phylogeny

Leyva-Díaz

Masoudi

Serrano-Saiz

et al. 2020

WIREs Developmental Biology

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One approach to understand the construction of complex systems is to investigate whether there are simple design principles that are commonly used in building such a system. In the context of nervous system development, one may ask whether the generation of its highly diverse sets of constituents, that is, distinct neuronal cell types, relies on genetic mechanisms that share specific common features. Specifically, are there common patterns in the function of regulatory genes across different neuron types and are those regulatory mechanisms not only used in different parts of one nervous system, but are they conserved across animal phylogeny? We address these questions here by focusing on one specific, highly conserved and well‐studied regulatory factor, the POU homeodomain transcription factor UNC‐86. Work over the last 30 years has revealed a common and paradigmatic theme of unc‐86 function throughout most of the neuron types in which Caenorhabditis elegans unc‐86 is expressed. Apart from its role in preventing lineage reiterations during development, UNC‐86 operates in combination with distinct partner proteins to initiate and maintain terminal differentiation programs, by coregulating a vast array of functionally distinct identity determinants of specific neuron types. Mouse orthologs of unc‐86, the Brn3 genes, have been shown to fulfill a similar function in initiating and maintaining neuronal identity in specific parts of the mouse brain and similar functions appear to be carried out by the sole Drosophila ortholog, Acj6. The terminal selector function of UNC‐86 in many different neuron types provides a paradigm for neuronal identity regulation across phylogeny. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Invertebrate Organogenesis > Worms Nervous System Development > Vertebrates: Regional Development

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A transcription factor collective defines the HSN serotonergic neuron regulatory landscape

Cited by 50 publications

References 110 publications

BRN3-type POU Homeobox Genes Maintain the Identity of Mature Postmitotic Neurons in Nematodes and Mice

BRN3-type POU Homeobox Genes Maintain the Identity of Mature Postmitotic Neurons in Nematodes and Mice

Loss of the Er81 Transcription Factor in Cholinergic Cells Alters Striatal Activity and Habit Formation

Brn3/POU‐IV‐type POU homeobox genes—Paradigmatic regulators of neuronal identity across phylogeny

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