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Results for “Germ Layers”

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At least 19 recordsLinked to original sources
PubMed2025

Foxi2 and Sox3 are master regulators controlling ectoderm germ layer specification.

In vertebrates, germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus. Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomics analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

Ep300↗
PubMed2025

Foxi2 and Sox3 are master transcription regulators that control ectoderm germ layer specification in Xenopus.

Germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus. Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomic analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification.

Animals↗
PubMed2025

Glycolytic activity instructs germ layer proportions through regulation of Nodal and Wnt signaling.

Metabolic pathways can influence cell fate decisions, yet their regulative role during embryonic development remains poorly understood. Here, we demonstrate an instructive role of glycolytic activity in regulating signaling pathways involved in mesoderm and endoderm specification. Using a mouse embryonic stem cell (mESC)-based in vitro model for gastrulation, we found that glycolysis inhibition increases ectodermal cell fates at the expense of mesodermal and endodermal lineages. We demonstrate that this relationship is dose dependent, enabling metabolic control of germ layer proportions through exogenous glucose levels. We further show that glycolysis acts as an upstream regulator of Nodal and Wnt signaling and that its influence on cell fate specification can be decoupled from its effects on growth. Finally, we confirm the generality of our findings using a human gastrulation model. Our work underscores the dependence of signaling pathways on metabolic conditions and provides mechanistic insight into the nutritional regulation of cell fate decision-making.

Glycolysis↗
PubMed1979

Fine structural differentiation of germ layers in the mouse at the time of mesoderm formation.

The morphology of early postimplantation mouse egg cylinders was studied using light and electron microscopy. Implantation sites at seven, seven and one-half and eight days of gestation were dissected from the myometrium and whole implants, including both decidua and egg cylinders were processed for electron microscopy. Pre-primitive streak egg cylinders were composed of two germ layers, a tall columnar ectoderm and an outer visceral endodermal layer. Ectodermal cells demonstrated large oval nuclei and an organelle sparse cytoplasm except for many free polyribosomes. The visceral endodermal layer was composed of two cell populations. One visceral endodermal cell type observed was tall columnar in shape and appeared absorptive as demonstrated by many microvilli, pinocytotic profiles and lysosomal granules. This population was confined to extraembryonic regions of the egg cylinder. The second visceral endodermal cell type, squamous in shape, evidenced only a few microvilli, pinocytotic profiles and lysosomal granules. This population was confined to the embryonic region of the egg cylinder. Concurrent with the formation of the primitive streak an increased number of cellular junctions and nuclear pores became evident in the ectoderm. Mesodermal cells were large and stellate-shaped exhibiting many filapodia which made contact with adjacent mesodermal elements. Later the cephalic region of the primitive streak proliferated resulting in the migration of wedge-shaped mass of cells, the head process. At the most ventral extremity of the post-primitive streak egg cylinder the cells of the head process became intimately associated with the ectoderm by areas of focal contact and gap junctions.

Animals↗
PubMed2025

Foxh1 is a locus-specific PRC2 recruiter governing germ layer silencing.

Polycomb Repressive Complex 2 (PRC2) establishes H3K27me3 marks to shape spatiotemporal gene expression during embryogenesis. While its dysregulation is linked to developmental disorders, cancer, and aging, the mechanisms guiding PRC2 to specific genomic loci remain a subject of ongoing debate. A prevailing model proposes that PRC2 recruitment occurs via its intrinsic affinity for chromatin rather than through sequence-specific transcription factors. Here, we provide evidence that the maternally deposited pioneer transcription factor Foxh1 plays a critical role in directing PRC2 to specific genomic loci during zygotic genome activation in Xenopus. Foxh1 is a critical transcription factor mediating Nodal signaling, but it also plays an earlier role by pre-binding enhancers prior to signaling activation. This pre-binding is essential for forming enhanceosome complexes that trigger mesendodermal gene expression and drive gastrulation, in cooperation with other maternal transcription factors. Using maternal Foxh1-null embryos, we demonstrate that Foxh1 directly recruits Ezh2, the catalytic subunit of PRC2, to Foxh1-bound loci. Loss of Foxh1 impairs Ezh2 recruitment, leading to a global reduction in H3K27me3. These findings support a dual-function model in which Foxh1 not only activates endodermal gene expression in endoderm, but also recruits PRC2 to silence the same genes in ectoderm. This dual activity of Foxh1 allows the spatially coordinated epigenetic states of the endodermal gene regulatory program during early embryogenesis.

CRISPR/Cas9↗
PubMed1978

[Changes in gastrulation processes during phylogenesis in the animal world].

While treating gastrulation only as the entoderm individualization and formation of a double layer germ we do not take into consideration the alterations which gastrulation process has undergone in phylogenesis of different animal types. On the other hand, if entoderm formation (in vertebrates--with discoblastula) is not included in the notion of gastrulation, it will result in a complete incompartibility of gastrulation processes in other groups of animal kingdom. In birds and mammals, gastrulation is a double phasic process: the first phase--entoderm individualization by means of delamination (in combination with immigration), double layer germ formation; the second phase--individualization of mesoderm and chorda from the epiblast composition, a triple layer germ formation, the axial complex germs formation. During phylogenesis of the animal kingdom not only means and mechanisms of gastrulation change but also the contents of the process. For example, in Chordata besides increase in number of germ layers, gastrulation also includes the formation of the axial germ complex. As a result of gastrulational rearrangements of the blastula cellular maternal, the gastrula cell complex (germ layers and germs) come into a new system of interrelationships owing to which architectonic organizational bases of each particular animal type is laid down.

Animals↗
PubMed1979

Basic principles of cellular organization.

The hypothesis is put forward that the division of the animal body into three germ layers represents not only histological, but also functional specialization, the ectoderm taking over functions through which the animal is in contact with, acted upon or reacts to the external world, the entoderm metabolism and the mesoderm architectural and mechanical organization. This is assumed to mean that the tasks of life have been divided into three large function domains at an early stage of multicellular evolution, each germ layer taking over one domain and developing largely independently of the other two in the further course of phylogeny. The germ layers are autonomous in their own spheres, giving the body, in effect, a tripartite government. The potentiality of conceptual thought is inherent in all germ layers, reaching a high state of development in the entoderm and mesoderm at a much earlier stage of development than in the ectoderm. The animal body, as a whole, is in control of all its biologic activities; it is a self-designing, self-developing and self-perpetuating entity. The control of cellular organization is a mesodermal task.

Animals↗
PubMed2026

Post-transcriptional regulation of Profilin-2 by microRNAs and RNA-binding proteins forms a critical regulatory node for early embryonic cell fate decisions.

Post-transcriptional control by RNA binding proteins (RBPs) and microRNAs play central roles in mRNA stability and translation, yet how RBPs and microRNAs coordinate in developmental time to regulate cell fate remains poorly understood. Here, we demonstrate that post-transcriptional regulation of the Profilin 2 (Pfn2) transcript is essential for differentiation of embryonic stem cells (ESCs) into the primary germ layer lineages. The Pfn2 3'untranslated region has both an Iron Regulatory Protein binding site (IRE) and a nearby binding site for ESC enriched microRNAs. Deletion of this microRNA site leads to increased PFN2 and reduced FGF signaling during pluripotency transition prior to germ layer formation. In contrast, deletion of the IRE leads to decreased PFN2, a Wnt signaling defect, reduced nuclear beta-catenin, and a subsequent block in mesendodermal lineages during early germ layer formation. We further find that loss of the IRE site results in a cell autonomous defect in Wnt signaling and mesendodermal differentiation. The IRE site acts to stabilize beta-catenin, as disruption of the site leads to reduced nuclear beta-catenin levels. Together, these findings reveal the Pfn2 microRNA-IRE regulatory axis as a critical post-transcriptional regulatory node governing the switch from pluripotency to somatic differentiation.

MicroRNAs↗
PubMed1975

The effect of ACTH and cortisone on the carbohydrate-protein complexes of different types of epithelium in relation to their embryological origin.

Using histochemical methods the authors studied the effect of ACTH and cortisone on carbohydrate-protein complexes of epithelial cells derived from 3 different germ layers. It has been shown that cortisone increased the intensity of PAS reaction in all types of the epithelium investigated. Changes in acid mucosubstances after treatment with cortisone were different. After the administration of ACTH the observed changes in epithelium were not parallel to the changes seen after treatment with cortisone.

Adrenocorticotropic Hormone↗
PubMed1975

The effect of ACTH and cortisone on basement membrane in relation to the embryological origin of the epithelium.

The changes of intensity of PAS reaction in basement membranes of epithelial cells derived from 3 different germ layers in rats after treatment with ACTH and cortisone were observed. After treatment with cortisone an increase of PAS reaction in all investigated basement membranes was observed. Influence of cortisone on all basement membranes was independent of the embryological origin. The results after treatment with ACTH were not uniform.

Adrenocorticotropic Hormone↗
PubMed2025

Enhancer remodeling by OTX2 directs specification and patterning of mammalian definitive endoderm.

The molecular mechanisms that drive essential patterning events in the mammalian embryo remain poorly understood. Analysis of transcription factor expression kinetics at peri-gastrulation stages of development suggest Otx2 as a candidate regulator of the definitive endoderm, the precursor of all gut-derived organs. Accordingly, timed OTX2 depletion in gastruloids or during directed differentiation results in abnormal definitive endoderm specification in mouse and human, characterized by altered expression of components and transcriptional targets of the canonical WNT signaling pathway, perturbed adhesion and migration programs, and de-repression of regulators of other lineages. These defects cumulate in impaired foregut formation. Mechanistically, OTX2 is required to activate a subset of endoderm-specific enhancers and to suppress select enhancers of other lineages, allowing timely exit from the primitive streak and correct specification of anterior endoderm. Our results establish OTX2 as an early gut regulator and suggest molecular principles underlying spatiotemporal cell identity conserved across germ layers and species.

Otx Transcription Factors↗
PubMed2026

Functions and mechanisms of BRCA1 in early embryonic development.

Breast Cancer Gene 1 (BRCA1) is a critical regulator of genome integrity whose dysfunction greatly increases lifetime risk of breast and ovarian cancers. While BRCA1 has been extensively studied in the contexts of adult biology and cancer, its diverse functions, including homologous recombination-mediated DNA repair, cell cycle checkpoint activation, protein ubiquitination, and transcriptional regulation, have many underexplored implications. In early embryonic development, the maternal-to-zygotic transition (MZT) and subsequent developmental processes place extraordinary demands on DNA replication fidelity, cell cycle regulation, transcriptional activation, and chromatin remodeling. These critical processes overlap strikingly with canonical functions of BRCA1, yet its function in early development is poorly characterized. In this review, we investigate BRCA1 conservation across species and connect its well-established functions to findings from developmental studies to assess its role in development. We highlight evidence of BRCA1 mitigating genome integrity loss from diverse sources, maintaining the proliferative activity needed for successful germ layer formation and early tissue morphogenesis, and regulating transcription and epigenetic modifications. Together, this synthesis supports a model where BRCA1 acts as a multi-functional and dynamic regulator of early embryogenesis. Building on this, we propose outstanding questions that could further illuminate these developmental roles. Characterization of BRCA1 in early development may not only provide important insight into the origin and progression of cancer susceptibility but may also elucidate fundamental mechanisms shaping early development.

BRCA1 Protein↗
PubMed2026

CRISPR/Cas9-mediated editing of ERCC6 in iPSCs: A disease model for Cockayne Syndrome type B.

Cockayne Syndrome type B (CSB) is caused by mutations in the ERCC6 gene, which encodes a key protein involved in transcription-coupled nucleotide excision repair (TC-NER) and chromatin remodeling. Deficiency in CSB leads to defective transcriptional recovery after DNA damage, oxidative stress accumulation, and progressive neurodegeneration. In this work, we generated a CRISPR/Cas9-engineered human induced pluripotent stem cell (iPSC) line, IUFi004-A-12, carrying a homozygous mutation in ERCC6 causing a premature stop codon in its 10th exon. The modified iPSCs displayed normal morphology, expressed pluripotency markers, and differentiated into all three germ layers. This model enables mechanistic studies of CSB dysfunction and facilitates therapeutic development for Cockayne Syndrome.

Humans↗
PubMed2026

Generation of an induced pluripotent stem cell line, LGMi002-A, from a Bardet-Biedl Syndrome patient with a BBS5 homozygous pathogenic variant.

The human induced pluripotent stem cell (iPSC) line, iPSC-BBS5stbg1, derived from a patient with a Bardet-Biedl Syndrome (BBS) phenotype and carrying a BBS5 homozygous pathogenic variant: c.123delA, p.Gly42Glufs*11 is described. The reprogramming of the patient's dermal fibroblasts was achieved using the non-integrative Sendai virus system delivering the OCT4, SOX2, KLF4 and c-MYC (OSKM) transcription factors. The established iPSC line iPSC-BBS5stbg1 displays typical iPSC morphology, maintains genomic stability, and demonstrates the ability to differentiate into cell types representative of the three embryonic germ layers. This iPSC line constitutes robust and relevant cellular model for studying BBS-associated disease mechanisms and ciliary dysfunction.

Humans↗
PubMed2026

CRISPR/Cpf1-mediated knockout of FLG in human induced pluripotent stem cells generates a model for studying epidermal barrier dysfunction.

Loss of filaggrin (FLG) function impairs skin barrier formation and contributes to common inflammatory skin diseases. In this study, we established a FLG knockout human induced pluripotent stem cell (iPSC) line based on KOLF2.1 J using CRISPR/Cas12a (Cpf1)-mediated genome editing. A guide RNA targeting exon 2 introduced a homozygous mutation, which was confirmed by sequencing. The edited cells maintained typical pluripotent stem cell morphology, expressed key undifferentiated markers, and retained the ability to differentiate into all three germ layers. Karyotype and copy number variation (CNV) analyses confirmed genomic stability and parental origin; the cells were free of mycoplasma. This cell line enables studies of FLG-associated skin biology and pathology.

Humans↗
PubMed2026

Establishment of four induced pluripotent stem cell lines (IGIBi028-A, IGIBi029-A, IGIBi030-A, and IGIBi031-A) from peripheral blood derived cells of Spinocerebellar ataxia Type 12 patients.

Spinocerebellar ataxia type 12 (SCA12) is a progressive late-onset neurodegenerative disorder caused by expansion of ≥ 43 trinucleotide CAG repeats in the upstream non-coding region of the PPP2R2B gene at locus 5q32 (SCA12; OMIM#604326). Clinically SCA12 patients predominately present hand tremor, gait ataxia, tremulous voice and other neurological and psychiatric features. Neuroimaging reveals degenerative changes in the cerebral cortex and cerebellum, however, the underlying disease mechanism at molecular level is still incompletely understood. Here we report generation of four induced pluripotent stem cells (iPSCs) of SCA12 patients. The established lines were positive for PPP2R2B-CAG expansion mutation and showed expression of undifferentiated hPSC state markers, three germ layer differentiation potential, normal genetic integrity and contamination-free culture.

Humans↗