Phuangphong S, Yoshikawa H, Kojima Y
… +2 more, Wada H, Morino Y
Development
· 2025 Apr · PMID 40105679
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The embryonic shell field of mollusks appears during gastrulation on the dorsal ectoderm and later develops into the adult shell-secreting mantle. Although several lines of evidence have revealed that the shell field is...The embryonic shell field of mollusks appears during gastrulation on the dorsal ectoderm and later develops into the adult shell-secreting mantle. Although several lines of evidence have revealed that the shell field is exclusively derived from the second quartet (2q) of 16-cell embryos, it is generally believed that its fate is established only after receiving inductive signals from cells derived from other quartets, such as the invaginated endoderm. However, the induction hypothesis remains questionable due to limited experimental evidence and contradictory results. Here, we re-investigated the induction hypothesis for shell field specification in the limpet. We identified three cell populations within the developing shell field using two-color in situ hybridization and single-cell transcriptome analysis, each characterized by distinct effector and transcription factor genes. The specification of each population was examined in 2q blastomeres isolated from 16-cell embryos. Even without inter-quartet interactions, marker gene expression for each shell field population was detected in the 2q-derived partial embryos. We conclude that the early specification of shell field in 2q-derived cells occurs largely independently of interactions with other quartets.
Wang K, Suyama R, Mizutani N
… +10 more, Matsuo M, Peng Y, Seki M, Suzuki Y, Luscombe NM, Dantec C, Lemaire P, Toyoda A, Nishida H, Onuma TA
Development
· 2025 Mar · PMID 40099490
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The larvacean Oikopleura dioica is a fast-developing chordate because of its small number of cells (∼4500 in juveniles) and rapid development to complete morphogenesis by 10 h after fertilization. Strikingly, most of its...The larvacean Oikopleura dioica is a fast-developing chordate because of its small number of cells (∼4500 in juveniles) and rapid development to complete morphogenesis by 10 h after fertilization. Strikingly, most of its blastomeres are restricted to give rise to a single cell-type by the 32-cell stage of embryogenesis, unlike cell fate determination at the 110-cell stage in ascidians. In this study, RNA-sequencing (RNA-seq) revealed non-canonical properties of O. dioica: (1) an initial zygotic gene expression of 950 genes at the 16- to 32-cell stage; (2) 25 transcription factors (TFs) are expressed in the 32-cell stage (fewer than half of the TFs underlying gene regulatory networks in ascidian embryogenesis were lost or not expressed); (3) five maternal mRNAs localized in the vegetal-posterior blastomeres in animal and vegetal hemispheres; and (4) three maternal mRNAs localized in the small vegetal pole region of unfertilized eggs. These observations indicate that this fast-developing chordate lacks the first phase of development in ascidians: fertilization-driven ooplasmic movements that drive postplasmic RNAs toward the vegetal pole. These data have been deposited in ANISEED (https://www.aniseed.fr/) as transcriptome resources.
Development
· 2025 Mar · PMID 40067309
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Condensates that accumulate small RNA biogenesis factors (nuage) are common in germ cells and often associate with nuclei. In the Caenorhabditis elegans germline, P granules overlay large clusters of nuclear pores and th...Condensates that accumulate small RNA biogenesis factors (nuage) are common in germ cells and often associate with nuclei. In the Caenorhabditis elegans germline, P granules overlay large clusters of nuclear pores and this organization has been proposed to facilitate surveillance of nascent transcripts by Argonaute proteins enriched in P granules. We report that co-clustering of nuclear pores and P granules depends on FG repeat-containing nucleoporins and FG repeats in the Vasa class helicase GLH-1. Worms with mutations that prevent this co-clustering are fertile under standard growth conditions and exhibit misregulation of only a minority of genes, including replication-dependent histones. Our observations suggest that association with nuclear pores, although non-essential for genome surveillance, may serve to tune mRNA flow through P granules and other nuage condensates.
Development
· 2025 Apr · PMID 40067261
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Gametogenesis is the process by which germ cells differentiate into mature sperm and oocytes - cells that are essential for sexual reproduction. The sex-specific molecular programs that drive spermatogenesis and oogenesi...Gametogenesis is the process by which germ cells differentiate into mature sperm and oocytes - cells that are essential for sexual reproduction. The sex-specific molecular programs that drive spermatogenesis and oogenesis can also serve as sex identification markers. Platynereis dumerilii is a research organism that has been studied in many areas of developmental biology. However, investigations often disregard sex, as P. dumerilii juveniles lack sexual dimorphism. The molecular mechanisms of gametogenesis in the segmented worm P. dumerilii are also largely unknown. In this study, we used RNA sequencing to investigate the transcriptomic profiles of gametogenesis in P. dumerilii juveniles. Our analysis revealed that sex-biased gene expression becomes increasingly pronounced during the advanced developmental stages, as worms approach maturation. We identified conserved genes associated with spermatogenesis, such as dmrt1, and with oogenesis, such as the previously unidentified gene psmt. Additionally, putative long non-coding RNAs were upregulated in both male and female gametogenic programs. This study provides a foundational resource for germ cell research in P. dumerilii and markers for sex identification, and offers comparative data to enhance our understanding of the evolution of gametogenesis mechanisms across species.
Alaniz-Fabián J, Xiang D, Del Toro-De León G
… +4 more, Gao P, Abreu-Goodger C, Datla R, Gillmor CS
Development
· 2025 Apr · PMID 40067256
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After fertilization in animals, maternal mRNAs and proteins regulate development until the onset of zygotic transcription. In plants, the extent of maternal regulation of early embryo development has been less clear: two...After fertilization in animals, maternal mRNAs and proteins regulate development until the onset of zygotic transcription. In plants, the extent of maternal regulation of early embryo development has been less clear: two hybrid combinations of rice zygotes have a strong maternal transcript bias, zygotes of a third rice hybrid produced by gamete fusion show a small percentage of maternally biased genes, while Arabidopsis Col/Cvi and Col/Ler hybrid embryos display symmetric and asymmetric parental genome activation, respectively. Here, we explore parent-of-origin transcriptome behavior in the Arabidopsis Col/Tsu hybrid, which was previously shown to display maternal effects for embryo defective mutants indistinguishable from those of the reference ecotype, Col. Analysis of Col/Tsu transcriptomes revealed a reciprocal maternal bias in thousands of genes in zygotes and octant stage embryos. Several lines of evidence suggest that this transient maternal bias is due to preferential transcription of maternal alleles in the zygote, rather than inheritance of transcripts from the egg. Our results extend previous observations that parent-of-origin contributions to early embryogenesis differ between hybrids of Arabidopsis, show that the maternal genome plays a predominant role in early embryos of Col/Tsu, and point to a maternal transcriptome bias in early embryos of the Arabidopsis reference ecotype Columbia.
Loh LS, DeMarr KA, Tsimba M
… +7 more, Heryanto C, Berrio A, Patel NH, Martin A, McMillan WO, Wray GA, Hanly JJ
Development
· 2025 Mar · PMID 40052482
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The success of butterflies and moths is tightly linked to the origin of scales within the group. A long-standing hypothesis postulates that scales are homologous to the well-described mechanosensory bristles found in the...The success of butterflies and moths is tightly linked to the origin of scales within the group. A long-standing hypothesis postulates that scales are homologous to the well-described mechanosensory bristles found in the fruit fly Drosophila melanogaster, as both derive from an epithelial precursor. Previous histological and candidate gene approaches identified parallels in genes involved in scale and bristle development. Here, we provide developmental and transcriptomic evidence that the differentiation of lepidopteran scales derives from the sensory organ precursor (SOP). Live imaging in lepidopteran pupae shows that SOP cells undergo two asymmetric divisions that first abrogate the neurogenic lineage, and then lead to a differentiated scale precursor and its associated socket cell. Single-nucleus RNA sequencing using early pupal wings revealed differential gene expression patterns that mirror SOP development, suggesting a shared developmental program. Additionally, we recovered a newly associated gene, the transcription factor pdm3, involved in the proper differentiation of butterfly wing scales. Altogether, these data open up avenues for understanding scale type specification and development, and illustrate how single-cell transcriptomics provide a powerful platform for understanding evolution of cell types.
Development
· 2025 Mar · PMID 40026193
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The E2F family of transcription factors is conserved in higher eukaryotes and plays pivotal roles in controlling gene expression during the cell cycle. Most canonical E2Fs associate with members of the Dimerisation Partn...The E2F family of transcription factors is conserved in higher eukaryotes and plays pivotal roles in controlling gene expression during the cell cycle. Most canonical E2Fs associate with members of the Dimerisation Partner (DP) family to activate or repress target genes. However, atypical repressors, such as E2F7 and E2F8, lack DP interaction domains and their functions are less understood. We report here that EFL-3, the E2F7 homologue of Caenorhabditis elegans, regulates epidermal stem cell differentiation. We show that phenotypic defects in efl-3 mutants depend on the Nemo-like kinase LIT-1. EFL-3 represses lit-1 expression through direct binding to a lit-1 intronic element. Increased LIT-1 expression in efl-3 mutants reduces POP-1/TCF nuclear distribution, and consequently alters Wnt pathway activation. Our findings provide a mechanistic link between an atypical E2F family member and NLK during C. elegans asymmetric cell division, which may be conserved in other animals.
Development
· 2025 Oct · PMID 40018816
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Sensory experience drives the maturation of neural circuits during postnatal brain development through molecular mechanisms that remain to be fully elucidated. One likely mechanism involves the sensory-dependent expressi...Sensory experience drives the maturation of neural circuits during postnatal brain development through molecular mechanisms that remain to be fully elucidated. One likely mechanism involves the sensory-dependent expression of genes that encode direct mediators of circuit remodeling within developing cells. To identify potential drivers of sensory-dependent synaptic development, we generated a single-nucleus RNA sequencing dataset describing the transcriptional responses of cells in the mouse visual cortex to sensory deprivation or to stimulation during a developmental window when visual input is necessary for circuit refinement. We sequenced 118,529 nuclei across 16 neuronal and non-neuronal cell types isolated from control, sensory deprived and sensory stimulated mice, identifying 1268 sensory-induced genes within the developing brain. While experience elicited transcriptomic changes in all cell types, excitatory neurons in layer 2/3 exhibited the most robust changes, and the sensory-induced genes in these cells are poised to strengthen synapse-to-nucleus crosstalk and to promote cell type-specific axon guidance pathways. Altogether, we expect this dataset to significantly broaden our understanding of the molecular mechanisms through which sensory experience shapes neural circuit wiring in the developing brain.
Pimmett VL, McGehee J, Trullo A
… +4 more, Douaihy M, Radulescu O, Stathopoulos A, Lagha M
Development
· 2025 Mar · PMID 40018801
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Morphogen gradients convey essential spatial information during tissue patterning. Although the concentration and timing of morphogen exposure are both crucial, how cells interpret these graded inputs remains challenging...Morphogen gradients convey essential spatial information during tissue patterning. Although the concentration and timing of morphogen exposure are both crucial, how cells interpret these graded inputs remains challenging to address. We employed an optogenetic system to acutely and reversibly modulate the nuclear concentration of the morphogen Dorsal (DL), homolog of NF-κB, which orchestrates dorsoventral patterning in the Drosophila embryo. By controlling DL nuclear concentration while simultaneously recording target gene outputs in real time, we identified a critical window for DL action that is required to instruct patterning and characterized the resulting effect on spatiotemporal transcription of target genes in terms of timing, coordination and bursting. We found that a transient decrease in nuclear DL levels at nuclear cycle 13 leads to reduced expression of the mesoderm-associated gene snail (sna) and partial derepression of the neurogenic ectoderm-associated target short gastrulation (sog) in ventral regions. Surprisingly, the mispatterning elicited by this transient change in DL was detectable at the level of single-cell transcriptional bursting kinetics, specifically affecting long inter-burst durations. Our approach of using temporally resolved and reversible modulation of a morphogen in vivo, combined with mathematical modeling, establishes a framework for understanding the stimulus-response relationships that govern embryonic patterning.
Nordin A, Zambanini G, Enar Jonasson M
… +4 more, Weiss T, van de Grift Y, Pagella P, Cantù C
Development
· 2025 Mar · PMID 40013513
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Gene regulators physically associate with the genome, in a combinatorial fashion, to drive tissue-specific gene expression. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to...Gene regulators physically associate with the genome, in a combinatorial fashion, to drive tissue-specific gene expression. Uncovering the genome-wide activity of all gene regulators across tissues is therefore needed to understand gene regulation during development. Here, we take a first step towards this goal. Using CUT&RUN, we systematically mapped genome-wide binding profiles of key transcription factors and co-factors that mediate ontogenetically relevant signaling pathways in select mouse tissues at two developmental stages. Computation of the datasets unveiled tissue- and time-specific activity for each gene regulator. We identified 'popular' regulatory regions that are bound by a multitude of regulators, which tend to be more evolutionarily conserved. Consistently, they lie near the transcription start site of genes for which dysregulation results in early embryonic lethality. Moreover, the human homologs of these regions are similarly bound by many gene regulators and are highly conserved, indicating a retained relevance for human development. This work constitutes a decisive step towards understanding how the genome is simultaneously read and used by gene regulators in a holistic fashion to drive embryonic development.
Marefati M, Fernandez-Vallone V, Leprovots M
… +8 more, Vasile G, Libert F, Lefort A, Dinsart G, Weber A, Jetzer J, Garcia MI, Vassart G
Development
· 2025 Apr · PMID 40013494
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Collagenase and dispase treatment of intestinal tissue from adult mice generates cells growing in matrigel as stably replatable cystic spheroids, in addition to differentiated organoids. Contrary to classical EDTA-derive...Collagenase and dispase treatment of intestinal tissue from adult mice generates cells growing in matrigel as stably replatable cystic spheroids, in addition to differentiated organoids. Contrary to classical EDTA-derived organoids, these spheroids display poor intestinal differentiation and grow independently of Rspondin, noggin and EGF. Their transcriptome strikingly resembles that of fetal intestinal spheroids, with downregulation of crypt base columnar cell (CBC) markers (Lgr5, Ascl2, Smoc2 and Olfm4). In addition, they display upregulation of inflammatory and mesenchymal genetic programs, together with robust expression of YAP target genes. Lineage tracing, cell-sorting and single cell RNA sequencing experiments demonstrate that adult spheroid-generating cells belong to a hitherto undescribed developmental lineage, independent of Lgr5-positive CBCs, and are involved in regeneration of the epithelium following CBC ablation.
Chen Q, Deng M, Zhao P
… +9 more, Rehmani MS, Cheng W, Wang S, Wang J, Wang C, Gao S, Yang B, Deyholos MK, Jiang YQ
Development
· 2025 Mar · PMID 40007462
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During leaf morphogenesis, various factors interplay to mediate abaxial-adaxial and proximal-distal polarity, along with other factors contributing to organ boundary and leaf expansion. Although significant progress has...During leaf morphogenesis, various factors interplay to mediate abaxial-adaxial and proximal-distal polarity, along with other factors contributing to organ boundary and leaf expansion. Although significant progress has been made in understanding the genetics of leaf development, there are still gaps in our understanding of leaf morphogenesis. Here, we show that the bHLH60 transcription factor can affect leaf development. Overexpression of bHLH60 leads to pleiotropic phenotypes with increased leaf serration and reduced fertility. A RNA-seq analysis showed that the BREVIPEDICELLUS1 (BP1) gene implicated in leaf development was upregulated as a result of bHLH60 overexpression. Further analysis revealed that bHLH60 directly bound to the BP1 promoter to activate its transcription. Subsequently, bHLH60 interacted with the repressor complex AS1-AS2 and JLO to relieve the inhibition of AS1-AS2 on BP1, thereby indirectly activating the expression of BP1. Genetic analysis indicated that the BP1 mutation partially suppressed the phenotype resulting from bHLH60 overexpression, thereby concluding that the pleiotropic phenotypes of bHLH60-overexpressing plants were partly dependent on BP1. We propose that bHLH60 competes with the AS1-AS2-JLO complex to regulate BP1 expression to modulate leaf development.
Lahti L, Volakakis N, Gillberg L
… +8 more, Yaghmaeian Salmani B, Tiklová K, Kee N, Lundén-Miguel H, Werkman M, Piper M, Gronostajski R, Perlmann T
Development
· 2025 Mar · PMID 39995267
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Correct timing of neurogenesis is crucial for generating the correct number and subtypes of glia and neurons in the embryo, and for preventing tumours and stem cell depletion in the adults. Here, we analyse how the midbr...Correct timing of neurogenesis is crucial for generating the correct number and subtypes of glia and neurons in the embryo, and for preventing tumours and stem cell depletion in the adults. Here, we analyse how the midbrain dopamine (mDA) neuron progenitors transition into cell cycle arrest (G0) and begin to mature into ependymal cells. Comparison of mDA progenitors from different embryonic stages revealed upregulation of the genes encoding Sox9 and nuclear factor I transcription factors during development. Their conditional inactivation in the early embryonic midbrain led to delayed G0 entry and ependymal maturation in the entire midbrain ventricular zone, reduced gliogenesis and increased generation of neurons, including mDA neurons. In contrast, their inactivation in late embryogenesis did not result in mitotic re-entry, suggesting that these factors are necessary for G0 induction, but not for its maintenance. Our characterisation of adult ependymal cells by single-cell RNA sequencing and histology show that mDA-progenitor-derived cells retain several progenitor features but also secrete neuropeptides and contact neighbouring cells and blood vessels, indicating that these cells may form part of the circumventricular organ system.
Lin Z, Rong B, Wu M
… +9 more, Yan J, Hong T, Hou L, Tang X, Liu Q, Peng X, Chen Y, Lan F, Tong MH
Development
· 2025 Mar · PMID 39992154
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ASH2L is a core component of KMT2 complexes, crucial for H3K4 trimethylation. However, its role in spermatogenesis remains elusive. Here, we demonstrate an essential role of Ash2l for meiotic prophase but dispensable for...ASH2L is a core component of KMT2 complexes, crucial for H3K4 trimethylation. However, its role in spermatogenesis remains elusive. Here, we demonstrate an essential role of Ash2l for meiotic prophase but dispensable for mitosis in differentiated spermatogonia. Using a germ cell-specific Ash2l knockout mouse model, we reveal that Ash2l deficiency leads to meiotic arrest and sterility in both sexes. Ash2l-deficient spermatocytes exhibit failures in chromosomal synapsis associated with persistent DMC1 foci and γH2AX, resulting in meiocyte loss due to apoptosis. Conversely, Ash2l-deficient differentiated spermatogonia show normal development. Mechanistically, Ash2l deficiency results in a global loss of H3K4me3 in promoter regions and significantly decreases expression of thousands of genes. Among these are genes involved in epigenetic silencing pathways, such as H3K9 di-methylation, DNA methylation and piRNA pathways, that are crucial for transposon repression during meiotic prophase I progression. Supporting this, we observe that Ash2l mutant spermatocytes display ectopic expression of LINE1-ORF1P. Our findings therefore reveal the previously unappreciated role of ASH2L-dependent H3K4me3 modification in spermatogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility.
Development
· 2025 Feb · PMID 39982400
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Understanding gene regulation in organism development is crucial in biology. Techniques like whole-mount in situ hybridization can reveal spatial gene expression in organs and tissues. However, capturing time-lapse movie...Understanding gene regulation in organism development is crucial in biology. Techniques like whole-mount in situ hybridization can reveal spatial gene expression in organs and tissues. However, capturing time-lapse movies of gene expression dynamics in embryos developing in utero, such as mice, remains technically challenging beyond the early stages. To address this, we present a method to integrate static snapshots of gene expression patterns across limb developmental stages, creating a continuous 2D reconstruction of gene expression patterns over time. This method interpolates small tissue regions over time to create smooth temporal trajectories of gene expression. We successfully applied it to a number of key genes in limb development, including Sox9, Hand2, and Bmp2. This approach enables a detailed spatio-temporal mapping of gene expression, providing insights into developmental mechanisms. By estimating gene expression patterns at previously unobserved time points, it facilitates the comparison of these patterns across samples. The reconstructed trajectories offer high-quality data that will be useful to guide computational modeling and machine learning, advancing the study of developmental biology in systems where real-time imaging is technically difficult or impossible.
Jia K, Cheng B, Huang L
… +5 more, Xu J, Liu F, Liao X, Liao K, Lu H
Development
· 2025 Mar · PMID 39976298
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Biliary epithelial cell (BEC)-derived liver regeneration in zebrafish exhibits similarities to liver regeneration in chronic liver injury. However, the underlying mechanisms remain poorly understood. Here, we identified...Biliary epithelial cell (BEC)-derived liver regeneration in zebrafish exhibits similarities to liver regeneration in chronic liver injury. However, the underlying mechanisms remain poorly understood. Here, we identified a serine peptidase called prolyl endopeptidase (Prep) as an indispensable factor during the BEC-derived liver regeneration process. prep was significantly upregulated and enriched in bipotential progenitor cells (BP-PCs). Through gain- and loss-of-function assays, prep was found to potently accelerate liver regeneration and drastically increase the proliferation of BP-PCs. Mechanistically, prep expression was directly regulated by ten-eleven translocation 2 (Tet2)-mediated DNA demethylation. More strikingly, Tet2 regulated prep expression by directly interacting and reducing the methylation of CpG sites in the prep promoter. Subsequently, Prep activated the PI3K-AKT-mTOR signaling pathway to regulate liver regeneration. Therefore, our study revealed the role and mechanism of Tet2-mediated DNA demethylation-associated upregulation of prep in the proliferation of BP-PCs during liver regeneration. These results identify promising targets for stimulating regeneration following chronic liver injury.
Samuels TJ, Torley EJ, Nadmitova V
… +4 more, Naden EL, Blair PE, Hernandez Frometa FA, Karam Teixeira F
Development
· 2025 Mar · PMID 39964294
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The tight control of the mitotic phase of differentiation is crucial to prevent tumourigenesis while securing tissue homeostasis. In the Drosophila female germline, differentiation involves precisely four mitotic divisio...The tight control of the mitotic phase of differentiation is crucial to prevent tumourigenesis while securing tissue homeostasis. In the Drosophila female germline, differentiation involves precisely four mitotic divisions, and accumulating evidence suggests that bag of marbles (bam), the initiator of differentiation, is also involved in controlling the number of divisions. To test this hypothesis, we depleted Bam from differentiating cells and found a reduced number of mitotic divisions. We examined the regulation of Bam using RNA imaging methods and found that the bam 3' UTR conveys instability to the transcript in the eight-cell cyst and early 16-cell cyst. We show that the RNA-binding protein Rbp9 is responsible for timing bam mRNA decay. Rbp9 itself is part of a sequential cascade of RNA-binding proteins activated downstream of Bam, and we show that it is regulated through a change in transcription start site, driven by Rbfox1. Altogether, we propose a model in which Bam expression at the beginning of differentiation initiates a series of events that eventually terminates the Bam expression domain.
Oliveira-Valença VM, Roberts JM, Fernandes-Cerqueira VM
… +9 more, Colmerauer CH, de Toledo BC, Santos-França PL, Linden R, Martins RAP, Rocha-Martins M, Bosco A, Vetter ML, da Silveira MS
Development
· 2025 Mar · PMID 39946314
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Retinal ganglion cells (RGCs) are the projection neurons of the retina, and their death promotes an irreversible blindness. Several factors were described to control their genesis during retinal development. These includ...Retinal ganglion cells (RGCs) are the projection neurons of the retina, and their death promotes an irreversible blindness. Several factors were described to control their genesis during retinal development. These include Atoh7, a major orchestrator of the RGC program, and downstream targets of this transcription factor, including Pou4f factors, that in turn regulate key aspects of terminal differentiation. The absence of POU4F family genes results in defects in RGC differentiation, aberrant axonal elaboration and, ultimately, RGC death. This confirms the requirement of POU4F factors for RGC development and survival, with a crucial role in regulating RGC axon outgrowth and pathfinding. Here, we have investigated in vivo whether ectopic Pou4f2 expression in late retinal progenitor cells (late RPCs) is sufficient to induce the generation of cells with RGC properties, including long-range axon projections. We show that Pou4f2 overexpression generates RGC-like cells that share morphological and transcriptional features with RGCs that are normally generated during early development and extend axonal projections up to the brain. In conclusion, these results show that POU4F2 alone is sufficient to promote the crucial properties of projection neurons that arise from retinal progenitors outside their developmental window.
Singh A, van den Burgh M, Boopathy V
… +4 more, van Nierop Y Sanchez P, Bageritz J, Lohmann I, Domsch K
Development
· 2025 Feb · PMID 39918891
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The evolutionarily conserved Hox genes define segment identities along the anterior-posterior axis and are expressed in most cell types within each segment, performing specific functions tailored to cellular needs. It ha...The evolutionarily conserved Hox genes define segment identities along the anterior-posterior axis and are expressed in most cell types within each segment, performing specific functions tailored to cellular needs. It has been suggested previously that Drosophila adult flight muscles in the second thoracic segment (T2) develop without direct Hox gene input, relying instead on ectodermal signals to shape their identity. However, our research, leveraging single-cell transcriptomics of Drosophila wing discs and Hox perturbation experiments using CRISPR technology and gain-of-function assays, unveiled a more intricate regulatory landscape. We found that the Hox protein Antennapedia (Antp) is essential for adult flight muscle development, acting in two crucial ways: by regulating the cell cycle rate of adult muscle precursors (AMPs) through repression of proliferation genes, and by guiding flight muscle fate via regulation of Hedgehog (Hh) signalling during cell fate establishment. Antp, along with its co-factor Apterous (Ap), directly interacts with the patched (ptc) locus to control its expression in AMPs. These findings challenge the notion of T2 as a 'Hox-free' zone, highlighting the indispensable role of low-level Antp expression in adult muscle development.
Hu X, He Y, Li S
… +9 more, Jiang Y, Yu R, Wu Y, Fu X, Song Y, Lin C, Shi J, Li HB, Gao Y
Development
· 2025 Feb · PMID 39817838
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Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A met...Hematopoietic development is tightly regulated by various factors. The role of RNA m6A modification during fetal hematopoiesis, particularly in megakaryopoiesis, remains unclear. Here, we demonstrate that loss of m6A methyltransferase METTL3 induces formation of double-stranded RNAs (dsRNAs) and activates acute inflammation during fetal hematopoiesis in mouse. This dsRNA-mediated inflammation leads to acute megakaryopoiesis, which facilitates the generation of megakaryocyte progenitors but disrupts megakaryocyte maturation and platelet production. The inflammation and immune response activate the phosphorylation of STAT1 and IRF3, and upregulate downstream interferon-stimulated genes (ISGs). Inflammation inhibits the proliferation rate of hematopoietic progenitors and further skews the cell fate determination toward megakaryocytes rather than toward erythroid from megakaryocyte-erythroid progenitors (MEPs). Transcriptional-wide gene expression analysis identifies IGF1 as a major factor whose reduction is responsible for the inhibition of megakaryopoiesis and thrombopoiesis. Restoration of IGF1 with METTL3-deficient hematopoietic cells significantly increases megakaryocyte maturation. In summary, we elucidate that the loss of RNA m6A modification-induced acute inflammation activates acute megakaryopoiesis, but impairs its final maturation through the inhibition of IGF1 expression during fetal hematopoiesis.