Postmitotic Hoxa5 Expression Specifies Pontine Neuron Positional Identity and Input Connectivity of Cortical Afferent Subsets

Maheshwari, Upasana; Kraus, Dominik; Vilain, Nathalie; Holwerda, Sjoerd; Cankovic, Vanja; Maiorano, Nicola A.; Kohler, Hubertus; Satoh, Daisuke; Sigrist, Markus W.; Arber, Silvia; Kratochwil, Claudius F.; Meglio, Thomas Di; Ducret, Sébastien; Rijli, Filippo M.

doi:10.1016/j.celrep.2020.107767

Cited by 12 publications

(21 citation statements)

References 105 publications

(113 reference statements)

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“…Different expression of Hox family genes is known to regulate segmentation of the rhombomere by controlling the expression of Eph receptors (Prin et al, 2014). Recently, Hox5-dependent positional identity of rostral pontine neurons and connectivity of somatosensory cortical afferents to the BP are shown (Maheshwari et al, 2020). We showed ectopic expression of EfnA5 in the rostral region of the BP in EphA7 À/À .…”

Section: Discussionmentioning

confidence: 61%

Mutually Repulsive EphA7–EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension

et al. 2021

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Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that EphA7 and EfnA5 are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, EphA7 and EfnA5 forward and reverse inhibitory signals direct collateral extension such that EphA7-positive frontal and occipital cortical areas extend their axon collaterals into the EfnA5-negative rostral part of the basilar pons, whereas EfnA5-positive parietal cortical areas extend their collaterals into the EphA7negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets.

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Section: Discussionmentioning

confidence: 61%

Mutually Repulsive EphA7–EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension

et al. 2021

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“…However, intrinsic differences in pontine neurons born at different times might also have an instructive role for corticopontine innervation. A recent study in mice showed that postmitotic expression of the HOX gene Hoxa5 guides pontine neurons to settle caudally within the pontine nuclei, where they are targeted by projections from limb representations in the somatosensory cortex (Maheshwari et al, 2020). Moreover, ectopic Hoxa5 expression in pontine neurons is sufficient to attract cortical somatosensory inputs, regardless of their spatial position in the pontine nuclei, showing that pontine neurons can play an instructive and attractive role in topographic input connectivity of corticopontine neurons (Maheshwari et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…Both structures need to be pre-patterned by gradient expression of transcription factors. While postmitotic pontine graded expression of Hoxa5 will impart an anterior to posterior identity to pontine neurons (graded blue circles) (Maheshwari et al, 2020), postmitotic cortical gradient expression of Nr2f1 (purple gradient in Ncx) will intrinsically instruct corticopontine neurons (dark and light purple tracts) to innervate their topographically proper targets (this study). Abbreviations: Cb, cerebellum; CP, cerebral peduncle; SC, spinal cord.…”

Section: Figure 8 Model Of Corticopontine Topography Establishment Proposed Schematic Model Of How the Neocortex (Ncx) And The Pontine Numentioning

confidence: 95%

“…The copyright holder for this preprint this version posted May 10, 2021. ; https://doi.org/10.1101/2021.05.10.443413 doi: bioRxiv preprint of sensory maps in several systems (D'Elia and Dasen, 2018, Erzurumlu et al, 2010, Fritzsch et al, 2019, McLaughlin and O'Leary, 2005, but whether this process is also operative during establishment of corticopontine topography is not completely understood. A recent study has shown that postmitotic graded expression of the HOX gene Hoxa5 is directly involved in imparting an anterior to posterior identity to pontine neurons, (Maheshwari et al, 2020), suggesting that pontine nuclei could play an instructive and attractive role in establishing corticopontine topographical organization. Whether expression in gradients of molecular factors along the antero-posterior (AP) or medio-lateral (ML) axes of the cerebral cortex also contributes to determine the topography of corticopontine projections is still not known.…”

Section: Introductionmentioning

confidence: 99%

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Topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1

Tocco

Øvsthus

Bjaalie

et al. 2021

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Axonal projections from layer V neurons of distinct neocortical areas are topographically organized into discrete clusters within the pontine nuclei during the establishment of voluntary movements. However, the molecular determinants controlling corticopontine connectivity are insufficiently understood. Here, we show that an intrinsic cortical genetic program driven by Nr2f1 graded expression in cortical progenitors and postmitotic neurons is directly implicated in the organization of corticopontine topographic mapping. Transgenic mice lacking cortical expression of Nr2f1 and exhibiting areal organization defects were used as model systems to investigate the arrangement of corticopontine projections. Combining three-dimensional digital brain atlas tools, Cre-dependent mouse lines, and axonal tracing, we show that Nr2f1 expression in postmitotic neurons spatially and temporally controls somatosensory topographic projections, whereas expression in progenitor cells influences the ratio between corticopontine and corticospinal fibers passing the pontine nuclei. We conclude that cortical gradients of area patterning genes are directly implicated in the establishment of a topographic somatotopic mapping from the cortex onto pontine nuclei.

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“…To obtain P8 Krox20::Cre;R26 Kir-mCherry ;r2::EGFP ( K20 Kir/+ ;r2 EGFP/+ ) mice, the Krox20::Cre;r2::EGFP mouse line was crossed with the R26 Kir-mCherry mouse line. Jmjd3 -/- ( Jmjd3KO ) mouse line was described previously 46 . To obtain P10 Krox20::Cre;LSL-R26 TVA-LaxZ ( K20 TVA/+ ) mouse, Krox20::Cre transgenic mouse line was crossed with LAL-R26 TVA-LacZ transgenic mouse line 47 , a kind gift of D. Saur.…”

Section: Methodsmentioning

confidence: 99%

A unique bipartite Polycomb signature regulates stimulus-response transcription during development

et al. 2021

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Rapid cellular responses to environmental stimuli are fundamental for development and maturation. Immediate early genes (IEGs) can be transcriptionally induced within minutes in response to a variety of signals. How their induction levels are regulated and their untimely activation by spurious signals prevented during development is poorly understood. We found that in developing sensory neurons, prior to perinatal sensory activity-dependent induction, IEGs are embedded into a unique bipartite Polycomb chromatin signature, carrying active H3K27ac on promoters but repressive Ezh2-dependent H3K27me3 on gene bodies. This bipartite signature is widely present in developing cell types, including embryonic stem cells (ESCs). Polycomb marking of gene bodies inhibits mRNA elongation, dampening productive transcription, while still allowing for fast stimulus-dependent mark removal and bipartite gene induction. We reveal a developmental epigenetic mechanism regulating rapidity and amplitude of the transcriptional response to relevant stimuli, while preventing inappropriate activation of stimulus-response genes.

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Postmitotic Hoxa5 Expression Specifies Pontine Neuron Positional Identity and Input Connectivity of Cortical Afferent Subsets

Cited by 12 publications

References 105 publications

Mutually Repulsive EphA7–EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension

Mutually Repulsive EphA7–EfnA5 Organize Region-to-Region Corticopontine Projection by Inhibiting Collateral Extension

Topography of corticopontine projections is controlled by postmitotic expression of the area-mapping gene Nr2f1

A unique bipartite Polycomb signature regulates stimulus-response transcription during development

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