Development最新文献

Neural crest induction begins early during neural plate formation, requiring precise transcriptional control to activate lineage-specific enhancers. Here, we demonstrate that SALL4, a transcription factor associated with syndromes featuring craniofacial anomalies, plays a crucial role in early cranial neural crest (CNCC) specification. Using SALL4-het-KO human iPSCs to model clinical haploinsufficiency, we show that SALL4 directly recruits BAF to CNCC-lineage specific enhancers at the neuroectodermal stage, specifically when neural crest gene expression is induced at the neural plate border. Without functional SALL4, BAF is not loaded at chromatin, leaving CNCC enhancers inaccessible. Consequently, the cells cannot undergo proper CNCC induction and specification due to persistent enhancer repression, despite normal neuroectodermal and neural plate progression. Moreover, by performing SALL4 isoform-specific depletion, we demonstrate that SALL4A is the isoform essential for CNCC induction and specification, and that SALL4B cannot compensate for SALL4A loss in this developmental process. In summary, our findings reveal SALL4 as essential regulator of BAF-dependent enhancer activation during early stages of neural crest development, providing molecular insights into SALL4-associated craniofacial anomalies.

Failure to close the cranial neural tube, known as exencephaly/anencephaly, is a lethal congenital defect. However, the mechanisms driving patterning and reshaping of the broad cranial neural folds are poorly understood. Loss of the primary cilium-localized G protein-coupled receptor GPR161 causes ectopic, excessive hedgehog signaling in the mouse neural tube and fully penetrant exencephaly. GPR161 promotes GLI3 transcriptional repressor (GLI3R) formation while preventing GLI2 transcriptional activator formation. Here, we studied the mechanisms underlying cranial closure in mice using a Gpr161 mutant allelic series, epistasis between Gpr161 knockout and GLI effectors, and in toto imaging of cell behavior. A functional non-ciliary Gpr161 knock-in implicated GPR161 ciliary localization directly in initiation and maintenance of cranial closure. Furthermore, Gli3R expression, but not Gli2 loss, rescued exencephaly in Gpr161 knockout mice. GLI3R specifically restricted forebrain ventral floor plate expansion and mediated apical constriction in the lateral midbrain neural folds prior to closure. These results reveal metamere-specific, cilia-dependent hedgehog repression thresholds in control of spatially restricted gene expression and dynamic cell behavior during cranial closure. Targeted interventions increasing hedgehog repression could ameliorate regional cranial defects.

Tissue maintenance in the presence of cell death-promoting insults requires a host of molecular mechanisms. Many studies focus on cell renewal through regeneration, while fewer studies explore mechanisms that promote cell longevity despite cell death stimuli. Here, we reveal that the adult Drosophila hindgut ileum is an excellent model for studying tissue maintenance by long-lived cells. Hindgut ileal enterocytes resist the damaging detergent SDS and upstream caspase signaling by head-involution-defective (hid). This hid-induced death insensitivity arises early in adulthood and is associated with numerous transcriptional changes. We interrogated 82 of these transcriptional changes in a candidate screen for enhancers of hid-induced death in the ileum. Top among our screen hits is an immunoglobulin family cell adhesion gene, CG15312, that maintains the adhesion protein FasIII on cell membranes. In hid-expressing ileal cells, CG15312 loss causes cell death and pyknotic nuclear clustering. We name this conserved gene low on-membrane fas and enhancer of hid (loofah). Our findings reveal a new mechanism linking cell adhesion and cell death resistance in a long-lived cell type. Our work establishes a new model for studying tissue preservation.

Cell fusion is vital for multi-nucleated cells to form during development. However, whether the process of cell fusion itself contributes to developmental gene regulation programmes is unclear. In a recent study, Owen Funk, Daniel (Dan) Levy and David Fay found that disrupting cell fusion protein EFF-1 in the multi-nucleated Caenorhabditis elegans epidermis impeded the transcriptional switch from embryonic to larval gene expression programmes and caused developmental delays, suggesting that cell fusion might regulate developmental progression. To learn more about how this paper developed and the people behind it, we talked to first author Owen Funk, and one of the corresponding authors, David Fay, Professor at the Department of Molecular Biology, University of Wyoming, WY, USA.

The functional gonads, essential for the continuity of a species, have both somatic and germline components. Newly formed germ cells are quiescent and are often physically isolated from the rest of the soma, protecting them from the signals that control somatic specification and differentiation. Nonetheless, the sequestered germ cells must ultimately navigate through the embryo to meet up with the somatic gonadal components. Forward genetic screens conducted in Drosophila have uncovered several crucial factors that generate both attractive and repulsive signals controlling germ cell movement. Efforts to reveal how the range of molecular players coordinate their activities to ensure that navigation is a robust and reproducible process have led to exciting, albeit sometimes contentious, discoveries. Herein, we summarize evidence for Hedgehog functioning in a single pathway from the signal source to signal reception to the downstream cytoskeletal events controlling the directed movement of germ cells to the site of gonad formation.

Between 2008 and 2025, four of The Company of Biologists' journals - Development, Journal of Cell Science (JCS), Journal of Experimental Biology (JEB) and Disease Models & Mechanisms (DMM) - offered Travelling Fellowships of up to £3000 to enable early-career researchers (ECRs) to make collaborative visits to other laboratories. Over the past few decades, these fellowships have enabled researchers within the communities served by the Company journals from all over the world to gain cutting-edge research experience, expand their professional networks and publish their findings - all of which has helped some of the former recipients to set up their own labs later in life. In this article, I trace the history of the Company's Travelling Fellowships scheme, initiated by Development and later expanded to include JCS, JEB and DMM, while also highlighting testimonials from former fellowship recipients and looking ahead to the Company's future plans.

Hematopoiesis occurs in three consecutive overlapping waves in mammals, regulated by transcription factors. We investigated the role of three relatively poorly studied transcription factors in early embryonic hematopoietic development at single-cell resolution: Atf3, Zfp711 and Bcl6b. These transcription factors are upregulated early in development, when hematopoietic and endothelial lineages separate from cardiac and other mesodermal lineages. We combined multiplexed single-cell RNA sequencing and flow cytometric analysis with knockouts in in vitro differentiating mouse embryonic stem cells to dissect the function of these transcription factors in lineage specification. ΔAtf3 cells showed increased mesodermal differentiation but decreased endothelial cells and erythro-myeloid progenitors, accompanied by aberrant interferon signaling. Mechanistically, loss of Atf3 disrupted key hematopoietic regulatory genes (Runx1, Egr1, Jun, Fos, Mafb and Batf3) required for the formation of erythro-myeloid progenitors. ΔZfp711 cells exhibited increased blood progenitors and erythroid cells, but decreased endothelial cells, with a striking shift from Hoxa+ mesoderm (allantois and limb mesoderm) to Hoxb+ mesoderm (mesenchyme and epicardium). Notably, Zfp711 binds the Atf3 promoter, suggesting a hierarchical regulation. In contrast, ΔBcl6b had no observable effects on early hematopoiesis, despite specific expression in hemato-endothelial progenitors.

In animals, species-specific organs and nervous systems are patterned from the developing neuroectoderm by conserved canonical Wnt signals. However, how these developmental trajectories diverged through evolution is unclear. Sébastien Darras and colleagues' new study on neuroectoderm patterning in ascidian embryos shows that the conserved Wnt signals elicit divergent molecular responses between species, suggesting that neuroectoderm patterning evolved at a molecular level. To learn more about how this research unfolded and the people behind it, we talked to first author Agnès Roure and corresponding author Sébastien Darras, Group Leader at Banyuls-sur-Mer Ocean Observatory in Sorbonne, France.