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1.
Nature ; 613(7943): 365-374, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36544019

RESUMO

How paternal exposure to ionizing radiation affects genetic inheritance and disease risk in the offspring has been a long-standing question in radiation biology. In humans, nearly 80% of transmitted mutations arise in the paternal germline1, but the transgenerational effects of ionizing radiation exposure has remained controversial and the mechanisms are unknown. Here we show that in sex-separated Caenorhabditis elegans strains, paternal, but not maternal, exposure to ionizing radiation leads to transgenerational embryonic lethality. The offspring of irradiated males displayed various genome instability phenotypes, including DNA fragmentation, chromosomal rearrangement and aneuploidy. Paternal DNA double strand breaks were repaired by maternally provided error-prone polymerase theta-mediated end joining. Mechanistically, we show that depletion of an orthologue of human histone H1.0, HIS-24, or the heterochromatin protein HPL-1, could significantly reverse the transgenerational embryonic lethality. Removal of HIS-24 or HPL-1 reduced histone 3 lysine 9 dimethylation and enabled error-free homologous recombination repair in the germline of the F1 generation from ionizing radiation-treated P0 males, consequently improving the viability of the F2 generation. This work establishes the mechanistic underpinnings of the heritable consequences of paternal radiation exposure on the health of offspring, which may lead to congenital disorders and cancer in humans.


Assuntos
Caenorhabditis elegans , Dano ao DNA , Reparo do DNA , Histonas , Animais , Humanos , Masculino , Caenorhabditis elegans/embriologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos da radiação , Dano ao DNA/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Histonas/metabolismo , Mutação , Radiação Ionizante , Perda do Embrião/genética , Feminino , Quebras de DNA de Cadeia Dupla/efeitos da radiação , Reparo do DNA por Junção de Extremidades
2.
Nature ; 613(7942): 153-159, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36517597

RESUMO

Sequential segmentation creates modular body plans of diverse metazoan embryos1-4. Somitogenesis establishes the segmental pattern of the vertebrate body axis. A molecular segmentation clock in the presomitic mesoderm sets the pace of somite formation4. However, how cells are primed to form a segment boundary at a specific location remains unclear. Here we developed precise reporters for the clock and double-phosphorylated Erk (ppErk) gradient in zebrafish. We show that the Her1-Her7 oscillator drives segmental commitment by periodically lowering ppErk, therefore projecting its oscillation onto the ppErk gradient. Pulsatile inhibition of the ppErk gradient can fully substitute for the role of the clock, and kinematic clock waves are dispensable for sequential segmentation. The clock functions upstream of ppErk, which in turn enables neighbouring cells to discretely establish somite boundaries in zebrafish5. Molecularly divergent clocks and morphogen gradients were identified in sequentially segmenting species3,4,6-8. Our findings imply that versatile clocks may establish sequential segmentation in diverse species provided that they inhibit gradients.


Assuntos
Padronização Corporal , MAP Quinases Reguladas por Sinal Extracelular , Periodicidade , Somitos , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Somitos/efeitos dos fármacos , Somitos/embriologia , Somitos/enzimologia , Somitos/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/antagonistas & inibidores , Proteínas de Peixe-Zebra/metabolismo , Relógios Biológicos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo
3.
Nature ; 612(7941): 732-738, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36517595

RESUMO

Our understanding of human early development is severely hampered by limited access to embryonic tissues. Due to their close evolutionary relationship with humans, nonhuman primates are often used as surrogates to understand human development but currently suffer from a lack of in vivo datasets, especially from gastrulation to early organogenesis during which the major embryonic cell types are dynamically specified. To fill this gap, we collected six Carnegie stage 8-11 cynomolgus monkey (Macaca fascicularis) embryos and performed in-depth transcriptomic analyses of 56,636 single cells. Our analyses show transcriptomic features of major perigastrulation cell types, which help shed light on morphogenetic events including primitive streak development, somitogenesis, gut tube formation, neural tube patterning and neural crest differentiation in primates. In addition, comparative analyses with mouse embryos and human embryoids uncovered conserved and divergent features of perigastrulation development across species-for example, species-specific dependency on Hippo signalling during presomitic mesoderm differentiation-and provide an initial assessment of relevant stem cell models of human early organogenesis. This comprehensive single-cell transcriptome atlas not only fills the knowledge gap in the nonhuman primate research field but also serves as an invaluable resource for understanding human embryogenesis and developmental disorders.


Assuntos
Gastrulação , Macaca fascicularis , Organogênese , Análise de Célula Única , Animais , Humanos , Camundongos , Gastrulação/genética , Macaca fascicularis/embriologia , Macaca fascicularis/genética , Organogênese/genética , Corpos Embrioides , Perfilação da Expressão Gênica , Linha Primitiva/citologia , Linha Primitiva/embriologia , Tubo Neural/citologia , Tubo Neural/embriologia , Crista Neural/citologia , Crista Neural/embriologia , Via de Sinalização Hippo , Mesoderma/citologia , Mesoderma/embriologia , Células-Tronco
4.
Science ; 378(6621): eabg3679, 2022 11 18.
Artigo em Inglês | MEDLINE | ID: mdl-36395225

RESUMO

The Hippo signaling pathway is widely considered a master regulator of organ growth because of the prominent overgrowth phenotypes caused by experimental manipulation of its activity. Contrary to this model, we show here that removing Hippo transcriptional output did not impair the ability of the mouse liver and Drosophila eyes to grow to their normal size. Moreover, the transcriptional activity of the Hippo pathway effectors Yap/Taz/Yki did not correlate with cell proliferation, and hyperactivation of these effectors induced gene expression programs that did not recapitulate normal development. Concordantly, a functional screen in Drosophila identified several Hippo pathway target genes that were required for ectopic overgrowth but not normal growth. Thus, Hippo signaling does not instruct normal growth, and the Hippo-induced overgrowth phenotypes are caused by the activation of abnormal genetic programs.


Assuntos
Drosophila melanogaster , Olho , Regulação da Expressão Gênica no Desenvolvimento , Via de Sinalização Hippo , Fígado , Transcrição Genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional , Proteínas de Sinalização YAP , Animais , Camundongos , Drosophila melanogaster/embriologia , Drosophila melanogaster/genética , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Olho/embriologia , Via de Sinalização Hippo/genética , Fígado/embriologia , Tamanho do Órgão , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transativadores/genética , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Proteínas de Sinalização YAP/metabolismo
5.
Cell Mol Life Sci ; 79(12): 609, 2022 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-36445537

RESUMO

The specification, characterization, and fate of alveolar type 1 and type 2 (AT1 and AT2) progenitors during embryonic lung development are poorly defined. Current models of distal epithelial lineage formation fail to capture the heterogeneity and dynamic contribution of progenitor pools present during early development. Furthermore, few studies explore the pathways involved in alveolar progenitor specification and fate. In this paper, we build upon our previously published work on the regulation of airway epithelial progenitors by fibroblast growth factor receptor 2b (FGFR2b) signalling during early (E12.5) and mid (E14.5) pseudoglandular stage lung development. Our results suggest that a significant proportion of AT2 and AT1 progenitors are lineage-flexible during late pseudoglandular stage development, and that lineage commitment is regulated in part by FGFR2b signalling. We have characterized a set of direct FGFR2b targets at E16.5 which are likely involved in alveolar lineage formation. These signature genes converge on a subpopulation of AT2 cells later in development and are downregulated in AT2 cells transitioning to the AT1 lineage during repair after injury in adults. Our findings highlight the extensive heterogeneity of pneumocytes by elucidating the role of FGFR2b signalling in these cells during early airway epithelial lineage formation, as well as during repair after injury.


Assuntos
Células Epiteliais Alveolares , Pulmão , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos , Células-Tronco , Animais , Camundongos , Desenvolvimento Embrionário , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Transdução de Sinais , Pulmão/embriologia , Linhagem da Célula
6.
Philos Trans R Soc Lond B Biol Sci ; 377(1865): 20210256, 2022 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-36252209

RESUMO

Implantation of the conceptus into the uterus is absolutely essential for successful embryo development. In humans, our understanding of this process has remained rudimentary owing to the inaccessibility of early implantation stages. Non-human primates recapitulate many aspects of human embryo development and provide crucial insights into trophoblast development, uterine receptivity and embryo invasion. Moreover, primate species exhibit a variety of implantation strategies and differ in embryo invasion depths. This review examines conservation and divergence of the key processes required for embryo implantation in different primates and in comparison with the canonical rodent model. We discuss trophectoderm compartmentalization, endometrial remodelling and embryo adhesion and invasion. Finally, we propose that studying the mechanism controlling invasion depth between different primate species may provide new insights and treatment strategies for placentation disorders in humans. This article is part of the theme issue 'Extraembryonic tissues: exploring concepts, definitions and functions across the animal kingdom'.


Assuntos
Implantação do Embrião , Primatas , Animais , Feminino , Gravidez , Endométrio/embriologia , Primatas/embriologia , Trofoblastos , Útero , Humanos
7.
Genetics ; 222(4)2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36218393

RESUMO

Transcription factors play important roles in the development of the intestinal epithelium and its ability to respond to endocrine, nutritional, and microbial signals. Hepatocyte nuclear factor 4 family nuclear receptors are liganded transcription factors that are critical for the development and function of multiple digestive organs in vertebrates, including the intestinal epithelium. Zebrafish have 3 hepatocyte nuclear factor 4 homologs, of which, hnf4a was previously shown to mediate intestinal responses to microbiota in zebrafish larvae. To discern the functions of other hepatocyte nuclear factor 4 family members in zebrafish development and intestinal function, we created and characterized mutations in hnf4g and hnf4b. We addressed the possibility of genetic redundancy amongst these factors by creating double and triple mutants which showed different rates of survival, including apparent early lethality in hnf4a; hnf4b double mutants and triple mutants. RNA sequencing performed on digestive tracts from single and double mutant larvae revealed extensive changes in intestinal gene expression in hnf4a mutants that were amplified in hnf4a; hnf4g mutants, but limited in hnf4g mutants. Changes in hnf4a and hnf4a; hnf4g mutants were reminiscent of those seen in mice including decreased expression of genes involved in intestinal function and increased expression of cell proliferation genes, and were validated using transgenic reporters and EdU labeling in the intestinal epithelium. Gnotobiotics combined with RNA sequencing also showed hnf4g has subtler roles than hnf4a in host responses to microbiota. Overall, phenotypic changes in hnf4a single mutants were strongly enhanced in hnf4a; hnf4g double mutants, suggesting a conserved partial genetic redundancy between hnf4a and hnf4g in the vertebrate intestine.


Assuntos
Fator 4 Nuclear de Hepatócito , Mucosa Intestinal , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Fator 4 Nuclear de Hepatócito/genética , Fator 4 Nuclear de Hepatócito/fisiologia , Mucosa Intestinal/embriologia , Mucosa Intestinal/metabolismo , Intestinos/embriologia , Intestinos/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/fisiologia
8.
Development ; 149(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36196625

RESUMO

Migration of myoblasts derived from the occipital somites is essential for tongue morphogenesis. However, the molecular mechanisms of myoblast migration remain elusive. In this study, we report that deletion of Isl1 in the mouse mandibular epithelium leads to aglossia due to myoblast migration defects. Isl1 regulates the expression pattern of chemokine ligand 12 (Cxcl12) in the first branchial arch through the Shh/Wnt5a cascade. Cxcl12+ mesenchymal cells in Isl1ShhCre embryos were unable to migrate to the distal region, but instead clustered in a relatively small proximal domain of the mandible. CXCL12 serves as a bidirectional cue for myoblasts expressing its receptor CXCR4 in a concentration-dependent manner, attracting Cxcr4+ myoblast invasion at low concentrations but repelling at high concentrations. The accumulation of Cxcl12+ mesenchymal cells resulted in high local concentrations of CXCL12, which prevented Cxcr4+ myoblast invasion. Furthermore, transgenic activation of Ihh alleviated defects in tongue development and rescued myoblast migration, confirming the functional involvement of Hedgehog signaling in tongue development. In summary, this study provides the first line of genetic evidence that the ISL1/SHH/CXCL12 axis regulates myoblast migration during tongue development.


Assuntos
Quimiocina CXCL12 , Proteínas Hedgehog , Proteínas com Homeodomínio LIM , Transdução de Sinais , Língua , Fatores de Transcrição , Animais , Camundongos , Movimento Celular/genética , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Ligantes , Transdução de Sinais/genética , Língua/embriologia , Proteínas com Homeodomínio LIM/genética , Fatores de Transcrição/genética , Quimiocina CXCL12/genética
9.
EMBO J ; 41(21): e111338, 2022 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-36121125

RESUMO

The balance between self-renewal and differentiation in human foetal lung epithelial progenitors controls the size and function of the adult organ. Moreover, progenitor cell gene regulation networks are employed by both regenerating and malignant lung cells, where modulators of their effects could potentially be of therapeutic value. Details of the molecular networks controlling human lung progenitor self-renewal remain unknown. We performed the first CRISPRi screen in primary human lung organoids to identify transcription factors controlling progenitor self-renewal. We show that SOX9 promotes proliferation of lung progenitors and inhibits precocious airway differentiation. Moreover, by identifying direct transcriptional targets using Targeted DamID, we place SOX9 at the centre of a transcriptional network, which amplifies WNT and RTK signalling to stabilise the progenitor cell state. In addition, the proof-of-principle CRISPRi screen and Targeted DamID tools establish a new workflow for using primary human organoids to elucidate detailed functional mechanisms underlying normal development and disease.


Assuntos
Pulmão , Fatores de Transcrição SOX9 , Células-Tronco , Humanos , Diferenciação Celular/fisiologia , Pulmão/embriologia , Transdução de Sinais , Fatores de Transcrição SOX9/metabolismo , Células-Tronco/metabolismo
10.
Science ; 377(6613): eabl3921, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36137018

RESUMO

The vertebrate intestine forms by asymmetric gut rotation and elongation, and errors cause lethal obstructions in human infants. Rotation begins with tissue deformation of the dorsal mesentery, which is dependent on left-sided expression of the Paired-like transcription factor Pitx2. The conserved morphogen Nodal induces asymmetric Pitx2 to govern embryonic laterality, but organ-level regulation of Pitx2 during gut asymmetry remains unknown. We found Nodal to be dispensable for Pitx2 expression during mesentery deformation. Intestinal rotation instead required a mechanosensitive latent transforming growth factor-ß (TGFß), tuning a second wave of Pitx2 that induced reciprocal tissue stiffness in the left mesentery as mechanical feedback with the right side. This signaling regulator, an accelerator (right) and brake (left), combines biochemical and biomechanical inputs to break gut morphological symmetry and direct intestinal rotation.


Assuntos
Gastrulação , Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Homeodomínio , Intestinos , Mecanotransdução Celular , Proteína Nodal , Fatores de Transcrição , Fator de Crescimento Transformador beta , Animais , Embrião de Galinha , Gastrulação/genética , Gastrulação/fisiologia , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/farmacologia , Intestinos/embriologia , Mecanotransdução Celular/genética , Mecanotransdução Celular/fisiologia , Camundongos , Proteína Nodal/genética , Fatores de Transcrição/genética , Fatores de Transcrição/farmacologia , Fator de Crescimento Transformador beta/metabolismo
12.
Science ; 377(6613): eabq5011, 2022 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-36137051

RESUMO

Recent evidence has shown that even mild mutations in the Huntingtin gene that are associated with late-onset Huntington's disease (HD) disrupt various aspects of human neurodevelopment. To determine whether these seemingly subtle early defects affect adult neural function, we investigated neural circuit physiology in newborn HD mice. During the first postnatal week, HD mice have less cortical layer 2/3 excitatory synaptic activity than wild-type mice, express fewer glutamatergic receptors, and show sensorimotor deficits. The circuit self-normalizes in the second postnatal week but the mice nonetheless develop HD. Pharmacologically enhancing glutamatergic transmission during the neonatal period, however, rescues these deficits and preserves sensorimotor function, cognition, and spine and synapse density as well as brain region volume in HD adult mice.


Assuntos
Encéfalo , Proteína Huntingtina , Doença de Huntington , Rede Nervosa , Neurogênese , Sinapses , Animais , Encéfalo/anormalidades , Modelos Animais de Doenças , Humanos , Proteína Huntingtina/genética , Doença de Huntington/embriologia , Doença de Huntington/genética , Camundongos , Camundongos Transgênicos , Rede Nervosa/anormalidades , Neurogênese/genética , Sinapses/fisiologia
13.
Nature ; 609(7929): 986-993, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36104568

RESUMO

Nutrients and energy have emerged as central modulators of developmental programmes in plants and animals1-3. The evolutionarily conserved target of rapamycin (TOR) kinase is a master integrator of nutrient and energy signalling that controls growth. Despite its key regulatory roles in translation, proliferation, metabolism and autophagy2-5, little is known about how TOR shapes developmental transitions and differentiation. Here we show that glucose-activated TOR kinase controls genome-wide histone H3 trimethylation at K27 (H3K27me3) in Arabidopsis thaliana, which regulates cell fate and development6-10. We identify FERTILIZATION-INDEPENDENT ENDOSPERM (FIE), an indispensable component of Polycomb repressive complex 2 (PRC2), which catalyses H3K27me3 (refs. 6-8,10-12), as a TOR target. Direct phosphorylation by TOR promotes the dynamic translocation of FIE from the cytoplasm to the nucleus. Mutation of the phosphorylation site on FIE abrogates the global H3K27me3 landscape, reprogrammes the transcriptome and disrupts organogenesis in plants. Moreover, glucose-TOR-FIE-PRC2 signalling modulates vernalization-induced floral transition. We propose that this signalling axis serves as a nutritional checkpoint leading to epigenetic silencing of key transcription factor genes that specify stem cell destiny in shoot and root meristems and control leaf, flower and silique patterning, branching and vegetative-to-reproduction transition. Our findings reveal a fundamental mechanism of nutrient signalling in direct epigenome reprogramming, with broad relevance for the developmental control of multicellular organisms.


Assuntos
Arabidopsis , Glucose , Alvo Mecanístico do Complexo 2 de Rapamicina , Fosfatidilinositol 3-Quinases , Desenvolvimento Vegetal , Complexo Repressor Polycomb 2 , Proteínas Repressoras , Transdução de Sinais , Arabidopsis/embriologia , Arabidopsis/enzimologia , Arabidopsis/genética , Arabidopsis/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica de Plantas , Inativação Gênica , Glucose/metabolismo , Histonas/química , Histonas/metabolismo , Alvo Mecanístico do Complexo 2 de Rapamicina/metabolismo , Mutação , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Desenvolvimento Vegetal/genética , Complexo Repressor Polycomb 2/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição/genética
14.
Eur Rev Med Pharmacol Sci ; 26(17): 6273-6282, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36111928

RESUMO

OBJECTIVE: L1  cell adhesion molecule (L1CAM) is a glycoprotein characterized by three components: an extracellular region, a transmembrane segment, and a cytoplasmic tail. L1CAM is expressed in multiple human cells, including neurons. The neural cell adhesion molecule L1 has been implicated in a variety of neurologic processes, including neuritogenesis and cerebellar cell migration. The presence of L1CAM on the surface of nerve cells allows the adhesion of neurons among them. Furthermore, when it is bound to itself or to other proteins, L1-CAM induces signals inside the cell. The aim of this work was to study L1CAM expression in the human spinal cord during development, at different gestational ages, through immunohistochemistry. MATERIALS AND METHODS: Immunohistochemical analysis for L1CAM was performed in five human spinal cord samples, including three embryos and two fetuses of different gestational ages, ranging from 8 to 12 weeks. RESULTS: L1CAM expression was detected in all 5 spinal cords examined in this study. The adhesion molecule was found in the vast majority of cells. The highest levels of immunoreactivity for L1CAM were detected at the periphery of the developing organs, in the spinal cord zones occupied by sensory and motor fibers. In the alar and basal columns, immunoreactivity for L1CAM was characterized by a reticular pattern, being mainly expressed in axons. Strong reactivity of L1CAM was also found in extracellular vesicles. This extracellular localization might indicate the ability of L1CAM to mediate the transduction of extracellular signals that support axon outgrowth. CONCLUSIONS: The high reactivity of L1cam in the axons of developing neurons in the fetal spinal cord confirms previous studies on the ability of L1CAM to promote axon sprouting and branching in the developing nervous system. In this work, a new actor is reported to have a role in the complex field of human spinal cord development: L1CAM, whose expression is highly found in the developing neuronal and glial precursors.


Assuntos
Vesículas Extracelulares , Molécula L1 de Adesão de Célula Nervosa , Medula Espinal , Axônios/metabolismo , Embrião de Mamíferos , Vesículas Extracelulares/metabolismo , Humanos , Lactente , Molécula L1 de Adesão de Célula Nervosa/genética , Molécula L1 de Adesão de Célula Nervosa/metabolismo , Medula Espinal/embriologia , Medula Espinal/crescimento & desenvolvimento , Medula Espinal/metabolismo
15.
Nature ; 609(7929): 1012-1020, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131015

RESUMO

Medulloblastoma, a malignant childhood cerebellar tumour, segregates molecularly into biologically distinct subgroups, suggesting that a personalized approach to therapy would be beneficial1. Mouse modelling and cross-species genomics have provided increasing evidence of discrete, subgroup-specific developmental origins2. However, the anatomical and cellular complexity of developing human tissues3-particularly within the rhombic lip germinal zone, which produces all glutamatergic neuronal lineages before internalization into the cerebellar nodulus-makes it difficult to validate previous inferences that were derived from studies in mice. Here we use multi-omics to resolve the origins of medulloblastoma subgroups in the developing human cerebellum. Molecular signatures encoded within a human rhombic-lip-derived lineage trajectory aligned with photoreceptor and unipolar brush cell expression profiles that are maintained in group 3 and group 4 medulloblastoma, suggesting a convergent basis. A systematic diagnostic-imaging review of a prospective institutional cohort localized the putative anatomical origins of group 3 and group 4 tumours to the nodulus. Our results connect the molecular and phenotypic features of clinically challenging medulloblastoma subgroups to their unified beginnings in the rhombic lip in the early stages of human development.


Assuntos
Linhagem da Célula , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Animais , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/embriologia , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Humanos , Meduloblastoma/classificação , Meduloblastoma/embriologia , Meduloblastoma/patologia , Metencéfalo/embriologia , Camundongos , Neurônios/patologia , Estudos Prospectivos
16.
Nature ; 609(7929): 1021-1028, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36131014

RESUMO

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1-4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5-8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+ unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.


Assuntos
Diferenciação Celular , Neoplasias Cerebelares , Meduloblastoma , Metencéfalo , Diferenciação Celular/genética , Linhagem da Célula , Neoplasias Cerebelares/classificação , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/patologia , Cerebelo/embriologia , Cerebelo/patologia , Subunidades alfa de Fatores de Ligação ao Core/genética , Proteínas Hedgehog/metabolismo , Histona Desmetilases , Humanos , Antígeno Ki-67/metabolismo , Meduloblastoma/classificação , Meduloblastoma/genética , Meduloblastoma/patologia , Metencéfalo/embriologia , Metencéfalo/patologia , Proteínas Musculares , Mutação , Fatores de Transcrição Otx/deficiência , Fatores de Transcrição Otx/genética , Proteínas Repressoras , Proteínas com Domínio T/metabolismo , Fatores de Transcrição
17.
Nature ; 610(7930): 190-198, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36131018

RESUMO

Although melanoma is notorious for its high degree of heterogeneity and plasticity1,2, the origin and magnitude of cell-state diversity remains poorly understood. Equally, it is unclear whether growth and metastatic dissemination are supported by overlapping or distinct melanoma subpopulations. Here, by combining mouse genetics, single-cell and spatial transcriptomics, lineage tracing and quantitative modelling, we provide evidence of a hierarchical model of tumour growth that mirrors the cellular and molecular logic underlying the cell-fate specification and differentiation of the embryonic neural crest. We show that tumorigenic competence is associated with a spatially localized perivascular niche, a phenotype acquired through an intercellular communication pathway established by endothelial cells. Consistent with a model in which only a fraction of cells are fated to fuel growth, temporal single-cell tracing of a population of melanoma cells with a mesenchymal-like state revealed that these cells do not contribute to primary tumour growth but, instead, constitute a pool of metastatic initiating cells that switch cell identity while disseminating to secondary organs. Our data provide a spatially and temporally resolved map of the diversity and trajectories of melanoma cell states and suggest that the ability to support growth and metastasis are limited to distinct pools of cells. The observation that these phenotypic competencies can be dynamically acquired after exposure to specific niche signals warrant the development of therapeutic strategies that interfere with the cancer cell reprogramming activity of such microenvironmental cues.


Assuntos
Proliferação de Células , Melanoma , Metástase Neoplásica , Animais , Comunicação Celular , Diferenciação Celular , Linhagem da Célula , Rastreamento de Células , Reprogramação Celular , Células Endoteliais , Melanoma/genética , Melanoma/patologia , Mesoderma/patologia , Camundongos , Metástase Neoplásica/patologia , Crista Neural/embriologia , Fenótipo , Análise de Célula Única , Transcriptoma , Microambiente Tumoral
18.
Proc Natl Acad Sci U S A ; 119(37): e2208465119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067310

RESUMO

Gene expression is tightly regulated by RNA-binding proteins (RBPs) to facilitate cell survival, differentiation, and migration. Previous reports have shown the importance of the Insulin-like Growth Factor II mRNA-Binding Protein (IGF2BP1/IMP1/ZBP1) in regulating RNA fate, including localization, transport, and translation. Here, we generated and characterized a knockout mouse to study RBP regulation. We report that IGF2BP1 is essential for proper brain development and neonatal survival. Specifically, these mice display disorganization in the developing neocortex, and further investigation revealed a loss of cortical marginal cell density at E17.5. We also investigated migratory cell populations in the IGF2BP1[Formula: see text] mice, using BrdU labeling, and detected fewer mitotically active cells in the cortical plate. Since RNA localization is important for cellular migration and directionality, we investigated the regulation of ß-actin messenger RNA (mRNA), a well-characterized target with established roles in cell motility and development. To aid in our understanding of RBP and target mRNA regulation, we generated mice with endogenously labeled ß-actin mRNA (IGF2BP1[Formula: see text]; ß-actin-MS2[Formula: see text]). Using endogenously labeled ß-actin transcripts, we report IGF2BP1[Formula: see text] neurons have increased transcription rates and total ß-actin protein content. In addition, we found decreased transport and anchoring in knockout neurons. Overall, we present an important model for understanding RBP regulation of target mRNA.


Assuntos
Actinas , Encéfalo , Proteínas de Ligação a RNA , Actinas/genética , Actinas/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Movimento Celular/genética , Camundongos , Camundongos Knockout , Neurônios/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo
19.
Proc Natl Acad Sci U S A ; 119(37): e2120079119, 2022 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-36067316

RESUMO

The extracellular protein Reelin, expressed by Cajal-Retzius (CR) cells at early stages of cortical development and at late stages by GABAergic interneurons, regulates radial migration and the "inside-out" pattern of positioning. Current models of Reelin functions in corticogenesis focus on early CR cell-derived Reelin in layer I. However, developmental disorders linked to Reelin deficits, such as schizophrenia and autism, are related to GABAergic interneuron-derived Reelin, although its role in migration has not been established. Here we selectively inactivated the Reln gene in CR cells or GABAergic interneurons. We show that CR cells have a major role in the inside-out order of migration, while CR and GABAergic cells sequentially cooperate to prevent invasion of cortical neurons into layer I. Furthermore, GABAergic cell-derived Reelin compensates some features of the reeler phenotype and is needed for the fine tuning of the layer-specific distribution of cortical neurons. In the hippocampus, the inactivation of Reelin in CR cells causes dramatic alterations in the dentate gyrus and mild defects in the hippocampus proper. These findings lead to a model in which both CR and GABAergic cell-derived Reelin cooperate to build the inside-out order of corticogenesis, which might provide a better understanding of the mechanisms involved in the pathogenesis of neuropsychiatric disorders linked to abnormal migration and Reelin deficits.


Assuntos
Córtex Cerebral , Proteínas do Tecido Nervoso , Neurônios , Proteína Reelina , Animais , Movimento Celular , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Neurônios GABAérgicos/enzimologia , Hipocampo/embriologia , Hipocampo/enzimologia , Interneurônios/enzimologia , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/enzimologia , Proteína Reelina/genética , Proteína Reelina/metabolismo
20.
Dev Dyn ; 251(12): 2015-2028, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36057966

RESUMO

BACKGROUND: Glypicans are a family of proteoglycans that play important roles in embryonic morphogenesis. The mammalian genome contains six glypicans (GPC1 to GPC6). GPC6 and GPC4 are the pair of glypicans that show the highest degree of homology within the family. GPC6-null embryos display bone abnormalities and severely shortened intestines. RESULTS: We show that GPC6-null embryos display significantly smaller stomachs, and that Hedgehog and noncanonical Wnt signaling are dysregulated in GPC6-null stomachs. Like GPC6, GPC4 is expressed by the developing stomach. However, GPC4-null embryos have normal stomachs. To investigate whether GPC6 and GPC4 display functional overlap in the developing stomach, we crossed GPC4-null mice with GPC6 conditional mutants in which the expression of this glypican is severely reduced in the stomach. Notably, we found that the compound mutants display stomachs that are smaller than those of the GPC6 conditional mutants. We also found that this functional overlap between GPC6 and GPC4 is mediated by the noncanonical Wnt pathway. CONCLUSION: This study demonstrates that GPC6 stimulates the growth of the embryonic stomach via Wnt and Hh signaling. In addition, we uncovered a Wnt-mediated functional overlap between GPC6 and GPC4 in the developing stomach.


Assuntos
Glipicanas , Proteínas Hedgehog , Estômago , Animais , Camundongos , Glipicanas/genética , Glipicanas/metabolismo , Proteínas Hedgehog/genética , Camundongos Knockout , Proteoglicanas/genética , Estômago/embriologia , Via de Sinalização Wnt
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