Biology subjects

Metzis, V.

Publications and source records attributed to Metzis, V..

6 recordsLinked to original sources

bioRxiv2026

Temporally distinct CDX programmes preconfigure vagal and trunk neural crest

Neural crest cells (NCCs) are progenitor cells vital in establishing the head, heart, gut and peripheral nervous system of vertebrate embryos. Disruptions to NCC development underlie neurocristopathies, which constitute a wide array of congenital anomalies. Yet how NCCs acquire defined regional identities that enable them to generate distinct derivatives along the body axis remains unclear. Here, we identify an epiblast progenitor population in mouse embryos that transiently contributes to vagal neural crest cells and trunk-to-tail derivatives. Using single-cell spatial transcriptomics across successive stages of neural crest migration, we generate a cervicothoracic cell atlas that resolves vagal and trunk neural crest cells in situ. Combining in vivo lineage tracing with in vitro models of neural crest induction, we show that despite transiently sharing a lineage, vagal and trunk neural crest arise through separate mechanisms. Temporally discrete regionalisation events mediated by CDX transcription factors establish HOX states that define vagal versus trunk identity. These findings revise models of NCC formation by demonstrating that temporally separate epiblast regionalisation events preconfigure neural crest and neural progenitor identities. More broadly, the results suggest that primary regionalisation events coordinately govern multiple cell lineages at the cervicothoracic transition, with implications for understanding neurocristopathies involving combined enteric and trunk derivatives.

developmental biology↗

bioRxiv2024

A dual enhancer-silencer element ensures transient Cdx2 expression during posterior body formation

During development, cells express precise gene expression programmes to assemble the trunk of the body plan. Appropriate control over the duration of the transcription factor Cdx2 is critical to achieve this outcome, yet, how cells control the onset, maintenance or termination of Cdx2, has remained unclear. Here, we delineate the cis-regulatory logic orchestrating dynamic Cdx2 expression in mouse caudal epiblast progenitors and their derivatives - spinal cord and presomitic mesoderm. Combining CRISPR-mediated deletion of regulatory elements with in vitro models and in vivo validation, we demonstrate that distinct enhancers, and a silencer, embedded at the Cdx2 locus, act sequentially to drive transient Cdx2 expression. We pinpoint a minimal silencer element that relies on a nuclear receptor motif to extinguish Cdx2. Changing this single motif converts the repressive element to an enhancer with opposite regulatory behaviour. Our findings elucidate design principles of developmental enhancers and silencers and establish a dual enhancer-silencer cis-regulatory logic ensuring precise spatiotemporal control over gene expression for vertebrate body patterning.

developmental biology↗

bioRxiv2020

Sox2 levels configure the WNT response of epiblast progenitors responsible for vertebrate body formation

WNT signalling has multiple roles. It maintains pluripotency of embryonic stem cells, assigns posterior identity in the epiblast and induces mesodermal tissue. We provide evidence that these distinct functions are conducted by the transcription factor SOX2, which adopts different modes of chromatin interaction and regulatory element selection depending on its level of expression. At high levels, SOX2 acts as a pioneer factor, displacing nucleosomes from regulatory elements with high affinity SOX2 binding sites and recruiting the WNT effector, TCF/{beta}-catenin, to maintain pluripotent gene expression. Reducing SOX2 levels destabilises pluripotency and reconfigures SOX2/TCF/{beta}-catenin occupancy to caudal epiblast expressed genes. These contain low-affinity SOX2 sites and are co-occupied by T/Bra and CDX. The loss of SOX2 allows WNT induced mesodermal differentiation. These findings define a role for Sox2 levels in dictating the chromatin occupancy of TCF/{beta}-catenin and reveal how context specific responses to a signal are configured by the level of a transcription factor.

developmental biology↗

bioRxiv2019

Precision of Tissue Patterning is Controlled by Dynamical Properties of Gene Regulatory Networks

During development, gene regulatory networks allocate cell fates by partitioning tissues into spatially organised domains of gene expression. How the sharp boundaries that delineate these gene expression patterns arise, despite the stochasticity associated with gene regulation, is poorly understood. We show, in the vertebrate neural tube, using perturbations of coding and regulatory regions, that the structure of the regulatory network contributes to boundary precision. This is achieved, not by reducing noise in individual genes, but by the configuration of the network modulating the ability of stochastic fluctuations to initiate gene expression changes. We use a computational screen to identify network properties that influence boundary precision, revealing two dynamical mechanisms by which small gene circuits attenuate the effect of noise in order to increase patterning precision. These results highlight design principles of gene regulatory networks that produce precise patterns of gene expression.

developmental biology↗

bioRxiv2019

ERK1/2 signalling dynamics promote neural differentiation by regulating the polycomb repressive complex

Fibroblast Growth Factor (FGF) is a neural inducer in many vertebrate embryos, but how it regulates chromatin organization to coordinate the activation of neural genes is unclear. Moreover, for differentiation to progress FGF signalling has to decline. Why this signalling dynamic is required has not been determined. Here we show that dephosphorylation of the FGF effector kinase ERK1/2 rapidly increases chromatin accessibility at neural genes in mouse embryos and, using ATAC-seq in human embryonic stem cell derived spinal cord precursors, we demonstrate that this occurs across hundreds of neural genes. Importantly, while Erk1/2 inhibition induces precocious neural gene transcription, this step involves dissociation of the polycomb repressive complex from gene loci and takes places independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. We find that loss of ERK1/2 activity but not its occupancy at neural genes is critical for this mechanism. Moreover, transient ERK1/2 inhibition is sufficient for polycomb protein dissociation and this is not reversed on resumption of ERK1/2 signalling. These data indicate that ERK1/2 signalling maintains polycomb repressive complexes at neural genes, that its decline coordinates their increased accessibility and that this is a directional molecular mechanism, which initiates the process of neural commitment. Furthermore, as the polycomb repressive complexes repress but also ready genes for transcription, these findings suggest that ERK1/2 promotion of these complexes is a rite of passage for subsequent differentiation.

developmental biology↗

bioRxiv2017

Regionalization of the nervous system requires axial allocation prior to neural lineage commitment

SummaryNeural induction in vertebrates generates a central nervous system that extends the rostral-caudal length of the body. The prevailing view is that neural cells are initially induced with anterior (forebrain) identity, with caudalising signals then converting a proportion to posterior fates (spinal cord). To test this model, we used chromatin accessibility assays to define how cells adopt region-specific neural fates. Together with genetic and biochemical perturbations this identified a developmental time window in which genome-wide chromatin remodeling events preconfigure epiblast cells for neural induction. Contrary to the established model, this revealed that cells commit to a regional identity before acquiring neural identity. This \"primary regionalization\" allocates cells to anterior or posterior regions of the nervous system, explaining how cranial and spinal neurons are generated at appropriate axial positions. These findings prompt a revision to models of neural induction and support the proposed dual evolutionary origin of the vertebrate central nervous system.

developmental biology↗