Development最新文献

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 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.

Precise transcriptional control is crucial for specifying neural crest lineages. In a new study, Demurtas et al. investigate the role of the transcription factor SALL4 in cranial neural crest cell specification, revealing a role in enhancer regulation. To find out more, we spoke to first author Martina Demurtas and corresponding author Marco Trizzino, Associate Professor at Imperial College London, UK.

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 striped expression of pair-rule genes in Drosophila embryos is a paradigm for understanding transcriptional control of development. Pair-rule striped expression is regulated by two types of cis-regulatory elements: stripe-specific elements respond to non-periodic cues in different regions of the embryo to establish individual stripes while 7-stripe elements simultaneously regulate all stripes, responding to pair-rule genes expressed in stripes. Here, we assess roles of stripe-specific versus 7-stripe elements for the pair-rule gene ftz. We show that loss of a ftz stripe 2 element is compensated by 7-stripe elements, even though they respond to different spatiotemporal cues. We next investigate whether similar rules apply to the classic eve stripe2 element. Animals homozygous for a genomic deletion of eve stripe2 are viable and fertile; stripe 2 expression is perturbed early but re-establishes sufficiently to regulate downstream target genes. However, temperature or genetic stress decrease viability of ftz and eve stripe 2 deletion mutants. Thus, these stripe-specific elements contribute to robustness but are not absolutely required for segment formation. Two separate routes to establishing stripes, stripe-specific and 7-stripe elements, buffer each other, adding complexity to embryonic patterning.

Organ patterning in plant shoots is influenced by the accumulation of the hormone auxin, driven by the polarisation of an auxin transporter protein. In a recent study, Kareem et al. investigated the role of transcription factor TMO5 in regulating this polarity and subsequent organogenesis. To find out more, we spoke to first author Abdul Kareem and corresponding author Marcus Heisler, Associate Professor at the University of Sydney, Australia.

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.