Building consensus in neuromesodermal research:Current advances and future biomedical perspectives

International audienceThe development of the vertebrate body axis relies on the activity of different populations of axial progenitors, including neuromesodermal progenitors. Currently, the term "Neuromesodermal progenitors'' is associated with various definitions. Here, we use distinct terminologies to highlight advances in our understanding of this cell type at both the single cell and population levels. We discuss how these recent insights prompt new opportunities to address a range of biomedical questions spanning cancer metastasis, congenital disorders, cellular metabolism, regenerative medicine, and evolution. Finally, we outline some of the major unanswered questions and propose future directions at the forefront of neuromesodermal research

Unmasking the ciliopathies: Craniofacial defects and the primary cilium

Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have been linked to ciliary assembly and/or function, demonstrating the importance of this organelle during embryonic development. Given the central role of the primary cilium in regulating developmental signaling, it is not surprising that its dysfunction results in widespread defects in the embryo, leading to an expanding class of human congenital disorders known as ciliopathies. These disorders are individually rare and phenotypically variable, but together they affect virtually every vertebrate organ system. Features of ciliopathies that are often overlooked, but which are being reported with increasing frequency, are craniofacial abnormalities, ranging from subtle midline defects to full-blown orofacial clefting. The challenge moving forward is to understand the primary mechanism of disease given the link between the primary cilium and a number of developmental signaling pathways (such as hedgehog, platelet-derived growth factor, and WNT signaling) that are essential for craniofacial development. Here, we provide an overview of the diversity of craniofacial abnormalities present in the ciliopathy spectrum, and reveal those defects in common across multiple disorders. Further, we discuss the molecular defects and potential signaling perturbations underlying these anomalies. This provides insight into the mechanisms leading to ciliopathy phenotypes more generally and highlights the prevalence of widespread dysmorphologies resulting from cilia dysfunction

Building consensus in Neuromesodermal Research: current advances and future biomedical perspectives

International audienceThe development of the vertebrate body axis relies on the activity of different populations of axial progenitors, including neuromesodermal progenitors. Currently, the term "Neuromesodermal progenitors'' is associated with various definitions. Here, we use distinct terminologies to highlight advances in our understanding of this cell type at both the single cell and population levels. We discuss how these recent insights prompt new opportunities to address a range of biomedical questions spanning cancer metastasis, congenital disorders, cellular metabolism, regenerative medicine, and evolution. Finally, we outline some of the major unanswered questions and propose future directions at the forefront of neuromesodermal research

Patched1 is essential for nasal pit invagination in mouse

Hedgehog (Hh) signalling plays a critical role in vertebrate face formation. To understand the role of the receptor Patched1 (PTCH1) in facial development, we are using the Wnt1–Cre to conditionally inactivate Ptch1 in neural crest cells. This results in constitutive, ligand-independent upregulation of the Hh pathway in the majority of mesenchymal cells in the face. We have shown for the first time that Ptch1 deletion drastically alters the shape of the nasal pit and disrupts its ability to invaginate. While neural crest cells are able to migrate and populate the developing nasal processes, they appear to form part of a loosely organised mesenchyme, unable to respond to FGF signals from the overlying epithelium and consequently fail to specify the lateral nasal process. We find that the structure of the overlying nasal pit epithelium is perturbed, evidenced by changes in cell–cell contacts and actin organisation. In summary, our analysis of Ptch1 conditional mutants has revealed unexpected changes in the shape and structure of cells of the nasal pit epithelium, which may explain why invagination is perturbed. These findings identify novel roles mediated by PTCH1 that are essential for correct morphogenesis of the nasal pit. Furthermore, they indicate that strict, spatio-temporal control of Hh signalling helps to define face shape in the embryo

ERK1/2 signalling dynamics promote neural differentiation by regulating chromatin accessibility and 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 must decline. Why these signalling dynamics are 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 genome-wide across neural genes. Importantly, ERK1/2 inhibition induces precocious neural gene transcription, and this involves dissociation of the polycomb repressive complex from key gene loci. This takes place independently of subsequent loss of the repressive histone mark H3K27me3 and transcriptional onset. Transient ERK1/2 inhibition is sufficient for the dissociation of the repressive complex, and this is not reversed on resumption of ERK1/2 signalling. Moreover, genomic footprinting of sites identified by ATAC-seq together with ChIP-seq for polycomb protein Ring1B revealed that ERK1/2 inhibition promotes the occupancy of neural transcription factors (TFs) at non-polycomb as well as polycomb associated sites. Together, these findings indicate that ERK1/2 signalling decline promotes global changes in chromatin accessibility and TF binding at neural genes by directing polycomb and other regulators and appears to serve as a gating mechanism that provides directionality to the process of differentiation

Mutations in DZIP1L, which encodes a ciliary-transition-zone protein, cause autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction. Here, we describe mutations in DZIP1L, which encodes DAZ interacting protein 1-like, in patients with ARPKD. We further validated these findings through loss-of-function studies in mice and zebrafish. DZIP1L localizes to centrioles and to the distal ends of basal bodies, and interacts with septin2, a protein implicated in maintenance of the periciliary diffusion barrier at the ciliary transition zone. In agreement with a defect in the diffusion barrier, we found that the ciliary-membrane translocation of the PKD proteins polycystin-1 and polycystin-2 is compromised in DZIP1L-mutant cells. Together, these data provide what is, to our knowledge, the first conclusive evidence that ARPKD is not a homogeneous disorder and further establish DZIP1L as a second gene involved in ARPKD pathogenesis

c-Maf controls immune responses by regulating disease-specific gene networks and repressing IL-2 in CD4+ T cells

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