Development最新文献

Hedgehog (HH) signalling is crucial for nervous system patterning. Genetic variants in key HH regulators, such as Gpr161, have been clinically linked to cranial neural tube closure defects (exencephaly) - a congenitally lethal condition. However, the role of Gpr161 in cranial neural tube closure remains unclear. In their latest study, Eric Brooks, Saikat Mukhopadhyay and colleagues present a substantial advance to our understanding of HH pathway logic across the developing murine nervous system by showing that ciliary GPR161 regulates HH signalling in different ways along the neural tube, with different consequences for cell remodelling and tube-closure. To learn more about this work and the people behind it, we talked to first author Sun-Hee Hwang, corresponding author Saikat Mukhopadhyay, and both first and corresponding author Eric Brooks.

The capacity to detect and respond to injury is crucial for the recovery and long-term survival of many organisms. Wnts are commonly induced by tissue damage but how they become activated transcriptionally is not well understood. Here, we report that mouse Wnt1 and Wnt10b are induced following injury in both lung and muscle. These Wnts occupy the same chromosome and are transcribed in opposite directions with 12 kb between them. We identified a highly conserved cis-acting regulatory region (enhancer) residing between Wnt1 and Wnt10b that, when fused to a lacZ reporter, is activated post-injury. This enhancer harbors putative AP-1-binding sites that are required for reporter activity, a feature observed in other injury-responsive enhancers. Injured muscles in mice carrying a germline deletion of the enhancer region display reduced Wnt1 and Wnt10b expression and show elevated intramuscular adipogenesis, which can be a hallmark of impaired muscle regeneration or tissue maintenance. Enhancer redundancy is common in development, but our in vivo analysis shows that loss of a single injury-responsive regulatory region in adult tissues can produce a detectable phenotype.

Cell fusion is a fundamental process in the development of many multicellular organisms, but its precise role in gene regulation and differentiation remains largely unknown. The Caenorhabditis elegans epidermis, which comprises multiple syncytial cells in the adult, represents a powerful model for studying cell fusion in the context of animal development. The largest of these epidermal syncytia, hyp7, integrates 139 individual nuclei through processive cell fusion mediated by the fusogenic protein EFF-1. To explore the role of cell fusion in developmental progression and associated gene expression changes, we conducted transcriptomic analyses of eff-1 fusion-defective C. elegans mutants. Our RNA-seq findings showed widespread transcriptomic changes including the enrichment of epidermal genes and molecular pathways involved in epidermal function during development. Single-molecule fluorescence in situ hybridization further validated the observed altered expression of mRNA transcripts. Moreover, bioinformatic analysis suggests that fusion may play a key role in promoting developmental progression within the epidermis. Our results underscore the significance of cell-cell fusion in shaping transcriptional programs during development.

Alejandro Torres-Sánchez is a group leader at EMBL Barcelona who uses theoretical and computational methods to understand fundamental principles of tissue self-organisation and shaping. In this interview, we talk to Alejandro about his path to becoming a group leader, ongoing collaborations and addressing gender imbalance in the lab.

Understanding the molecular mechanisms driving lineage decisions and differentiation during development is challenging in complex systems with a diverse progenitor pool, such as the mammalian cerebellum. Importantly, how different transcription factors cooperate to generate neural diversity and the gene regulatory mechanisms that drive neuron production, especially during the late stages of cerebellum development, are poorly understood. We used single cell RNA-sequencing (scRNA-seq) to investigate the developmental trajectories of nestin-expressing progenitors (NEPs) in the neonatal mouse cerebellum. We identified FOXO1 as a key regulator of NEP-to-inhibitory neuron differentiation, acting directly downstream of ASCL1. Genome occupancy and functional experiments using primary NEP cultures showed that both ASCL1 and FOXO1 regulate neurogenesis genes during differentiation while independently regulating proliferation and survival, respectively. Furthermore, we demonstrated that WNT signalling promotes the transition from an ASCL1+ to a FOXO1+ cellular state. Finally, the role of WNT signalling in promoting neuron production via FOXO1 is conserved in primary human NEP cultures. By resolving how cerebellar inhibitory neurons differentiate, our findings could have implications for cerebellar disorders such as spinocerebellar ataxia, where these cells are overproduced.

The striped gene expression pattern of the pair-rule genes along the Drosophila embryo requires tight coordination by regulatory elements. In a recent study, Fischer et al. reveal that regulatory elements with overlapping functions show compensatory mechanisms in driving the expression of two pair-rule genes: eve and ftz. To find out more, we spoke to first author Matthew Fischer and corresponding author Leslie Pick, Professor at the University of Maryland, USA.

During the regeneration of injured or lost tissues, the regeneration blastema serves as a hub for robust growth. Drosophila imaginal discs are a genetically tractable and simple model system for the study of regeneration and organization of this regrowth. Key signals that contribute to regenerative growth in these discs, such as reactive oxygen species, Wnt/Wg, JNK, p38, JAK/STAT and the Hippo pathway, have been identified. However, a detailed exploration of the spatial organization of regrowth, the factors that directly drive this growth, and the consequences of activating drivers of regeneration has not been undertaken. Here, we find that regenerative growth in imaginal discs is controlled by the transcription factor Myc and by Tor signaling, which drive proliferation and translation in the regeneration blastema. The spatial organization of growth in the blastema is arranged into concentric growth zones defined by Myc expression, elevated Tor activity and elevated translation. In addition, the increased Myc expression in the innermost zone induced Xrp1-independent cell competition-like death in the adjacent zones, revealing a delicate balance between driving growth and inducing death in the regenerating tissue.

The kidney is a complex organ requiring tightly coordinated interactions between epithelial, endothelial and mesenchymal cells during development. Congenital kidney defects can result in kidney disease and renal failure, highlighting the importance of understanding kidney formation mechanisms. Advances in RNA sequencing have revealed remarkable cellular heterogeneity, especially in the kidney stroma, although relationships between stromal, epithelial and endothelial cells remain unclear. This study presents a comprehensive gene expression atlas of embryonic and postnatal kidneys, integrating single-nucleus and in situ RNA sequencing data. We developed the Kidney Spatial Transcriptome Analysis Tool (KSTAT), enabling researchers to identify cell locations, predict cell-cell communication and map gene pathway activity. Using KSTAT, we were able to uncover significant heterogeneity among embryonic kidney pericytes, providing an important resource for hypothesis generation and advancing knowledge of kidney development and disease.

The network of transcription factors is dynamically reorganized during the transition from naïve- to formative-pluripotency. In mice, Prdm14 is expressed in naïve pluripotent cells but rapidly downregulated upon exit from the naïve state. In contrast, PRDM14 expression persists throughout pluripotency transitions in non-rodent mammals, including pigs and humans. Here, we investigate the molecular mechanisms underlying the rodent-specific expression of Prdm14. Using CRISPR/Cas9-mediated deletions, we demonstrated that POU5F1 and TFCP2L1 recognition sequences within Muroidea-specific cis-regulatory elements located downstream of Prdm14 are essential for its transcriptional upregulation in naïve embryonic stem cells. Loss of these enhancers attenuates the upregulation of Prdm14, leading to reduced Pramel7 induction and impaired degradation of UHRF1, which consequently diminished global DNA demethylation under 2iL conditions. Moreover, deletion of PRDM14-binding motifs in Muroidea-specific enhancers disrupts its negative feedback loop, resulting in a delayed transition from the naïve to formative pluripotent state. Our findings reveal that rodent-specific enhancer insertions endow Prdm14 with a dynamic regulatory architecture, enabling both activation and repression that collectively ensure the timely exit from naïve pluripotency during early embryogenesis.

Neural tube closure (NTC) is a conserved morphogenetic process in chordates in which the neural plate folds and fuses to form a closed neural tube. While the mechanical forces and signaling pathways governing NTC have been characterized in vertebrates, the transcriptional programs coordinating these behaviors remain less understood. Here, we identify a transcriptional circuit involving Lmx1, Cdkn1b and Msx that regulates dorsal midline dynamics during NTC in the tunicate Ciona. High-resolution HCR in situ hybridization reveals that Lmx1 expression is dynamically enriched at the zippering point and advances in a posterior-to-anterior transcription wave, while Msx is downregulated in the same region, marking a transition from early neural patterning to morphogenesis. As closure progresses, Lmx1 and Cdkn1b exhibit complementary, alternating expression at the dorsal midline, resembling a pair-rule-like pattern. Misexpression experiments show that Lmx1 promotes proliferation and autoregulates, whereas Cdkn1b limits proliferation and impedes closure. Single-cell RNA-seq datasets reveal transcriptionally distinct dorsal neural populations enriched for Lmx1 or Cdkn1b. This transcriptional switch coordinates proliferation and fusion during NTC, suggesting a general strategy for regulating epithelial remodeling in animal embryos.