E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner

Dréau, Gwenvaël Le; Escalona, René; Fueyo, Raquel; Herrera, Antonio; Usieto, Susana; Menéndez, Anghara; Pons, Sebastián; Martínez‐Balbás, Marian A.; Martı́, Elisa

doi:10.7554/elife.37267

Cited by 26 publications

(36 citation statements)

References 63 publications

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“…Still very little is known about how these gradients are established within the hindbrain [43], and how hindbrain progenitors interpret the quantitative information encoded by the concentration and duration of exposure to gradients. An alternative explanation is that different E proteins may control the ability of atoh1a to instruct dorsal or ventral neural progenitor cells to produce specific, specialized neurons, and thus ensure that the distinct types of neurons are produced in appropriate amounts as it happens in the chick spinal cord [44].…”

Section: Discussionmentioning

confidence: 99%

The interplay of atoh1 genes in the lower rhombic lip during hindbrain morphogenesis

2020

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The Lower Rhombic Lip (LRL) is a transient neuroepithelial structure of the dorsal hindbrain, which expands from r2 to r7, and gives rise to deep nuclei of the brainstem, such as the vestibular and auditory nuclei and most posteriorly the precerebellar nuclei. Although there is information about the contribution of specific proneural-progenitor populations to specific deep nuclei, and the distinct rhombomeric contribution, little is known about how progenitor cells from the LRL behave during neurogenesis and how their transition into differentiation is regulated. In this work, we investigated the atoh1 gene regulatory network operating in the specification of LRL cells, and the kinetics of cell proliferation and behavior of atoh1a-derivatives by using complementary strategies in the zebrafish embryo. We unveiled that atoh1a is necessary and sufficient for specification of LRL cells by activating atoh1b, which worked as a differentiation gene to transition progenitor cells towards neuron differentiation in a Notch-dependent manner. This cell state transition involved the release of atoh1a-derivatives from the LRL: atoh1a progenitors contributed first to atoh1b cells, which are committed non-proliferative precursors, and to the lhx2b-neuronal lineage as demonstrated by cell fate studies and functional analyses. Using in vivo cell lineage approaches we revealed that the proliferative cell capacity, as well as the mode of division, relied on the position of the atoh1a progenitors within the dorsoventral axis. We showed that atoh1a may behave as the cell fate selector gene, whereas atoh1b functions as a neuronal differentiation gene, contributing to the lhx2b neuronal population. atoh1a-progenitor cell dynamics (cell proliferation, cell differentiation, and neuronal migration) relies on their position, demonstrating the challenges that progenitor cells face in computing positional information from a dynamic two-dimensional grid in order to generate the stereotyped neuronal structures in the embryonic hindbrain.

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Section: Discussionmentioning

confidence: 99%

The interplay of atoh1 genes in the lower rhombic lip during hindbrain morphogenesis

2020

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“…Still very little is known about how these gradients are established within the hindbrain [35], and how hindbrain progenitors interpret the quantitative information encoded by the concentration and duration of exposure to gradients. An alternative explanation is that different E proteins may control the ability of atoh1a to instruct dorsal or ventral neural progenitor cells to produce specific, specialized neurons, and thus ensure that the distinct types of neurons are produced in appropriate amounts as it happens in the chick spinal cord [36].…”

Section: Discussionmentioning

confidence: 99%

The role ofatoh1genes in the development of the lower rhombic lip during zebrafish hindbrain morphogenesis

Belzunce

Pujades

2019

Preprint

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BACKGROUND: The Lower Rhombic Lip (LRL) is a transient neuroepithelial structure of the dorsal hindbrain, which expands from r2 to r7, and gives rise to deep nuclei of the brainstem, such as the vestibular and auditory nuclei and most posteriorly the precerebellar nuclei. Although there is information about the contribution of specific proneural-progenitor populations to specific deep nuclei, and the distinct rhombomeric contribution, little is known about how progenitor cells from the LRL behave during neurogenesis and how their transition into differentiation is regulated. RESULTS:In this work, we investigated the atoh1 gene regulatory network operating in the specification of LRL cells, and the kinetics of cell proliferation and behavior of atoh1a-derivatives by using complementary strategies in the zebrafish embryo. We unveiled that atoh1a is necessary and sufficient for specification of LRL cells by activating atoh1b, which worked as a differentiation gene to transition progenitor cells towards neuron differentiation in a Notch-dependent manner. This cell state transition involved the release of atoh1a-derivatives from the LRL: atoh1a progenitors contributed first to atoh1b cells, which are committed non-proliferative precursors, and to the lhx2bneuronal lineage as demonstrated by cell fate studies and functional analyses. Using in vivo cell lineage approaches we showed that the proliferative cell capacity, as well as their mode of division, relied on the position of the atoh1a progenitors within the dorsoventral axis.CONCLUSIONS: Our data demonstrates that the zebrafish provides an excellent model to study the in vivo behavior of distinct progenitor populations to the final neuronal differentiated pools, and to reveal the subfunctionalization of ortholog genes. Here, we unveil that atoh1a behaves as the cell fate selector gene, whereas atoh1b functions as a neuronal differentiation gene, contributing to the lhx2b neuronal population. atoh1aprogenitor cell dynamics (cell proliferation, cell differentiation, and neuronal migration) relies on their position, demonstrating the challenges that progenitor cells face in computing positional information from a dynamic two-dimensional grid in order to generate the stereotyped neuronal structures in the embryonic hindbrain. BACKGROUNDThe assembly of functional neural circuits requires the specification of neuronal identities and the execution of developmental programs that establish precise neural network wiring. The generation of such cell diversity happens during embryogenesis, at the same time that the brain undergoes a dramatic transformation from a simple tubular structure, the neural tube, to a highly convoluted structure -the brain-, resulting in changes in the position of neuronal progenitors and their derivatives upon time. Thus, the coordination of progenitor proliferation and cell fate specification is central to tissue growth and maintenance. The comprehension of how neuronal heterogeneity is achieved implies the understanding of how the neurogenic capaci...

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“…Conversely, signaling pathways promoting astrocytic fate impair the ability of proneural TFs to induce neuronal differentiation. BMP7, which is secreted from the dorsal telencephalic midline ( Furuta et al, 1997 ) induces Id1 or Id2 expression in spinal cord and cortical NPCs ( Vinals et al, 2004 ; Le Dreau et al, 2018 ). Id proteins inhibit proneural gene function by sequestering E proteins to prevent their heterodimerization with bHLH TFs ( Le Dreau et al, 2018 ).…”

Section: Intersection Between Proneural Genes and Extracellular Signamentioning

confidence: 99%

“…BMP7, which is secreted from the dorsal telencephalic midline ( Furuta et al, 1997 ) induces Id1 or Id2 expression in spinal cord and cortical NPCs ( Vinals et al, 2004 ; Le Dreau et al, 2018 ). Id proteins inhibit proneural gene function by sequestering E proteins to prevent their heterodimerization with bHLH TFs ( Le Dreau et al, 2018 ). Furthermore, Id1 induced by BMP4 promotes Ascl1 protein degradation to prevent this TF from promoting neuronal differentiation ( Vinals et al, 2004 ).…”

Section: Intersection Between Proneural Genes and Extracellular Signamentioning

confidence: 99%

“…E47 has been shown to preferentially bind CAGSTG motifs (where S = C/G) ( Lin et al, 2010 ; Pfurr et al, 2017 ). Recently it has been shown that E proteins alter the neurogenic strength of proneural TFs through physical interactions in a context-specific, E-box-dependent manner, by either synergizing with Ascl1 on CAGSTG motifs or impeding Neurog2’s binding to CADATG motifs ( Le Dreau et al, 2018 ). For example, misexpression of E47 and Ascl1 in spinal cord NPCs increases differentiation relative to Ascl1 alone ( Le Dreau et al, 2018 ), but the opposite effect is observed for co-electroporation of E47 with Neurog2 , either in spinal ( Le Dreau et al, 2018 ) or cortical ( Li et al, 2012 ) NPCs.…”

Section: Regulation Of Proneural Gene Function At the Translational Amentioning

confidence: 99%

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New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

Oproescu

Han

Schuurmans

2021

Front. Mol. Neurosci.

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Historically, the mammalian brain was thought to lack stem cells as no new neurons were found to be made in adulthood. That dogma changed ∼25 years ago with the identification of neural stem cells (NSCs) in the adult rodent forebrain. However, unlike rapidly self-renewing mature tissues (e.g., blood, intestinal crypts, skin), the majority of adult NSCs are quiescent, and those that become ‘activated’ are restricted to a few neurogenic zones that repopulate specific brain regions. Conversely, embryonic NSCs are actively proliferating and neurogenic. Investigations into the molecular control of the quiescence-to-proliferation-to-differentiation continuum in the embryonic and adult brain have identified proneural genes encoding basic-helix-loop-helix (bHLH) transcription factors (TFs) as critical regulators. These bHLH TFs initiate genetic programs that remove NSCs from quiescence and drive daughter neural progenitor cells (NPCs) to differentiate into specific neural cell subtypes, thereby contributing to the enormous cellular diversity of the adult brain. However, new insights have revealed that proneural gene activities are context-dependent and tightly regulated. Here we review how proneural bHLH TFs are regulated, with a focus on the murine cerebral cortex, drawing parallels where appropriate to other organisms and neural tissues. We discuss upstream regulatory events, post-translational modifications (phosphorylation, ubiquitinylation), protein–protein interactions, epigenetic and metabolic mechanisms that govern bHLH TF expression, stability, localization, and consequent transactivation of downstream target genes. These tight regulatory controls help to explain paradoxical findings of changes to bHLH activity in different cellular contexts.

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E proteins sharpen neurogenesis by modulating proneural bHLH transcription factors’ activity in an E-box-dependent manner

Cited by 26 publications

References 63 publications

The interplay of atoh1 genes in the lower rhombic lip during hindbrain morphogenesis

The interplay of atoh1 genes in the lower rhombic lip during hindbrain morphogenesis

The role ofatoh1genes in the development of the lower rhombic lip during zebrafish hindbrain morphogenesis

New Insights Into the Intricacies of Proneural Gene Regulation in the Embryonic and Adult Cerebral Cortex

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