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16 pages, 4540 KiB

Open AccessArticle

Kub3 Deficiency Causes Aberrant Late Embryonic Lung Development in Mice by the FGF Signaling Pathway

by Guangying Yang, Shan Lu, Jia Jiang, Jun Weng and Xiaomei Zeng

Int. J. Mol. Sci. 2022, 23(11), 6014; https://doi.org/10.3390/ijms23116014 - 27 May 2022

Cited by 1 | Viewed by 2114

Abstract

As a Ku70-binding protein of the KUB family, Kub3 has previously been reported to play a role in DNA double-strand break repair in human glioblastoma cells in glioblastoma patients. However, the physiological roles of Kub3 in normal mammalian cells remain unknown. In the [...] Read more.

As a Ku70-binding protein of the KUB family, Kub3 has previously been reported to play a role in DNA double-strand break repair in human glioblastoma cells in glioblastoma patients. However, the physiological roles of Kub3 in normal mammalian cells remain unknown. In the present study, we generated Kub3 gene knockout mice and revealed that knockout (KO) mice died as embryos after E18.5 or as newborns immediately after birth. Compared with the lungs of wild-type (WT) mice, Kub3 KO lungs displayed abnormal lung morphogenesis and pulmonary atelectasis at E18.5. No difference in cell proliferation or cell apoptosis was detected between KO lungs and WT lungs. However, the differentiation of alveolar epithelial cells and the maturation of type II epithelial cells were impaired in KO lungs at E18.5. Further characterization displayed that Kub3 deficiency caused an abnormal FGF signaling pathway at E18.5. Taking all the data together, we revealed that Kub3 deletion leads to abnormal late lung development in mice, resulting from the aberrant differentiation of alveolar epithelial cells and the immaturation of type II epithelial cells due to the disturbed FGF signaling pathway. Therefore, this study has uncovered an essential role of Kub3 in the prenatal lung development of mice which advances our knowledge of regulatory factors in embryonic lung development and provides new concepts for exploring the mechanisms of disease related to perinatal lung development. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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15 pages, 2697 KiB

Open AccessArticle

Inhibition of RhoA and Cdc42 by miR-133a Modulates Retinoic Acid Signalling during Early Development of Posterior Cardiac Tube Segment

by Carlos Garcia-Padilla, Virginio Garcia-Lopez, Amelia Aranega, Diego Franco, Virginio Garcia-Martinez and Carmen Lopez-Sanchez

Int. J. Mol. Sci. 2022, 23(8), 4179; https://doi.org/10.3390/ijms23084179 - 10 Apr 2022

Cited by 4 | Viewed by 2341

Abstract

It is well known that multiple microRNAs play crucial roles in cardiovascular development, including miR-133a. Additionally, retinoic acid regulates atrial marker expression. In order to analyse the role of miR-133a as a modulator of retinoic acid signalling during the posterior segment of heart [...] Read more.

It is well known that multiple microRNAs play crucial roles in cardiovascular development, including miR-133a. Additionally, retinoic acid regulates atrial marker expression. In order to analyse the role of miR-133a as a modulator of retinoic acid signalling during the posterior segment of heart tube formation, we performed functional experiments with miR-133a and retinoic acid by means of microinjections into the posterior cardiac precursors of both primitive endocardial tubes in chick embryos. Subsequently, we subjected embryos to whole mount in situ hybridisation, immunohistochemistry and qPCR analysis. Our results demonstrate that miR-133a represses RhoA and Cdc42, as well as Raldh2/Aldh1a2, and the specific atrial markers Tbx5 and AMHC1, which play a key role during differentiation. Furthermore, we observed that miR-133a upregulates p21 and downregulates cyclin A by repressing RhoA and Cdc42, respectively, thus functioning as a cell proliferation inhibitor. Additionally, retinoic acid represses miR-133a, while it increases Raldh2, Tbx5 and AMHC1. Given that RhoA and Cdc42 are involved in Raldh2 expression and that they are modulated by miR-133a, which is influenced by retinoic acid signalling, our results suggest the presence of a negative feedback mechanism between miR-133a and retinoic acid during early development of the posterior cardiac tube segment. Despite additional unexplored factors being possible contributors to this negative feedback mechanism, miR-133a might also be considered as a potential therapeutic tool for the diagnosis, therapy and prognosis of cardiac diseases. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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10 pages, 5100 KiB

Open AccessArticle

In Vivo and In Vitro Cartilage Differentiation from Embryonic Epicardial Progenitor Cells

by Paul Palmquist-Gomes, Ernesto Marín-Sedeño, Adrián Ruiz-Villalba, Gustavo Adolfo Rico-Llanos, José María Pérez-Pomares and Juan Antonio Guadix

Int. J. Mol. Sci. 2022, 23(7), 3614; https://doi.org/10.3390/ijms23073614 - 25 Mar 2022

Cited by 2 | Viewed by 2424

Abstract

The presence of cartilage tissue in the embryonic and adult hearts of different vertebrate species is a well-recorded fact. However, while the embryonic neural crest has been historically considered as the main source of cardiac cartilage, recently reported results on the wide connective [...] Read more.

The presence of cartilage tissue in the embryonic and adult hearts of different vertebrate species is a well-recorded fact. However, while the embryonic neural crest has been historically considered as the main source of cardiac cartilage, recently reported results on the wide connective potential of epicardial lineage cells suggest they could also differentiate into chondrocytes. In this work, we describe the formation of cardiac cartilage clusters from proepicardial cells, both in vivo and in vitro. Our findings report, for the first time, cartilage formation from epicardial progenitor cells, and strongly support the concept of proepicardial cells as multipotent connective progenitors. These results are relevant to our understanding of cardiac cell complexity and the responses of cardiac connective tissues to pathologic stimuli. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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15 pages, 2849 KiB

Open AccessArticle

The Embryonic Key Pluripotent Factor NANOG Mediates Glioblastoma Cell Migration via the SDF1/CXCR4 Pathway

by Ana Virginia Sánchez-Sánchez, Antonio García-España, Pilar Sánchez-Gómez, Jaime Font-de-Mora, Marián Merino and José Luis Mullor

Int. J. Mol. Sci. 2021, 22(19), 10620; https://doi.org/10.3390/ijms221910620 - 30 Sep 2021

Cited by 11 | Viewed by 2540

Abstract

NANOG is a key transcription factor required for maintaining pluripotency of embryonic stem cells. Elevated NANOG expression levels have been reported in many types of human cancers, including lung, oral, prostate, stomach, breast, and brain. Several studies reported the correlation between NANOG expression [...] Read more.

NANOG is a key transcription factor required for maintaining pluripotency of embryonic stem cells. Elevated NANOG expression levels have been reported in many types of human cancers, including lung, oral, prostate, stomach, breast, and brain. Several studies reported the correlation between NANOG expression and tumor metastasis, revealing itself as a powerful biomarker of poor prognosis. However, how NANOG regulates tumor progression is still not known. We previously showed in medaka fish that Nanog regulates primordial germ cell migration through Cxcr4b, a chemokine receptor known for its ability to promote migration and metastasis in human cancers. Therefore, we investigated the role of human NANOG in CXCR4-mediated cancer cell migration. Of note, we found that NANOG regulatory elements in the CXCR4 promoter are functionally conserved in medaka fish and humans, suggesting an evolutionary conserved regulatory axis. Moreover, CXCR4 expression requires NANOG in human glioblastoma cells. In addition, transwell assays demonstrated that NANOG regulates cancer cell migration through the SDF1/CXCR4 pathway. Altogether, our results uncover NANOG-CXCR4 as a novel pathway controlling cellular migration and support Nanog as a potential therapeutic target in the treatment of Nanog-dependent tumor progression. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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16 pages, 5104 KiB

Open AccessArticle

NEUROD1 Is Required for the Early α and β Endocrine Differentiation in the Pancreas

by Romana Bohuslavova, Ondrej Smolik, Jessica Malfatti, Zuzana Berkova, Zaneta Novakova, Frantisek Saudek and Gabriela Pavlinkova

Int. J. Mol. Sci. 2021, 22(13), 6713; https://doi.org/10.3390/ijms22136713 - 23 Jun 2021

Cited by 24 | Viewed by 4128

Abstract

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex [...] Read more.

Diabetes is a metabolic disease that involves the death or dysfunction of the insulin-secreting β cells in the pancreas. Consequently, most diabetes research is aimed at understanding the molecular and cellular bases of pancreatic development, islet formation, β-cell survival, and insulin secretion. Complex interactions of signaling pathways and transcription factor networks regulate the specification, growth, and differentiation of cell types in the developing pancreas. Many of the same regulators continue to modulate gene expression and cell fate of the adult pancreas. The transcription factor NEUROD1 is essential for the maturation of β cells and the expansion of the pancreatic islet cell mass. Mutations of the Neurod1 gene cause diabetes in humans and mice. However, the different aspects of the requirement of NEUROD1 for pancreas development are not fully understood. In this study, we investigated the role of NEUROD1 during the primary and secondary transitions of mouse pancreas development. We determined that the elimination of Neurod1 impairs the expression of key transcription factors for α- and β-cell differentiation, β-cell proliferation, insulin production, and islets of Langerhans formation. These findings demonstrate that the Neurod1 deletion altered the properties of α and β endocrine cells, resulting in severe neonatal diabetes, and thus, NEUROD1 is required for proper activation of the transcriptional network and differentiation of functional α and β cells. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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Review

Jump to: Research, Other

11 pages, 1092 KiB

Open AccessReview

Exploring the Origin and Physiological Significance of DNA Double Strand Breaks in the Developing Neuroretina

by Noemí Álvarez-Lindo, Teresa Suárez and Enrique J. de la Rosa

Int. J. Mol. Sci. 2022, 23(12), 6449; https://doi.org/10.3390/ijms23126449 - 9 Jun 2022

Cited by 3 | Viewed by 2178

Abstract

Genetic mosaicism is an intriguing physiological feature of the mammalian brain that generates altered genetic information and provides cellular, and prospectively functional, diversity in a manner similar to that of the immune system. However, both its origin and its physiological significance remain poorly [...] Read more.

Genetic mosaicism is an intriguing physiological feature of the mammalian brain that generates altered genetic information and provides cellular, and prospectively functional, diversity in a manner similar to that of the immune system. However, both its origin and its physiological significance remain poorly characterized. Most, if not all, cases of somatic mosaicism require prior generation and repair of DNA double strand breaks (DSBs). The relationship between DSB generation, neurogenesis, and early neuronal cell death revealed by our studies in the developing retina provides new perspectives on the different mechanisms that contribute to DNA rearrangements in the developing brain. Here, we speculate on the physiological significance of these findings. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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13 pages, 1546 KiB

Open AccessReview

Regulation of Epicardial Cell Fate during Cardiac Development and Disease: An Overview

by Cristina Sanchez-Fernandez, Lara Rodriguez-Outeiriño, Lidia Matias-Valiente, Felicitas Ramirez de Acuña, Francisco Hernandez-Torres, Estefania Lozano-Velasco, Jorge N. Dominguez, Diego Franco and Amelia Eva Aranega

Int. J. Mol. Sci. 2022, 23(6), 3220; https://doi.org/10.3390/ijms23063220 - 16 Mar 2022

Cited by 11 | Viewed by 3448

Abstract

The epicardium is the outermost cell layer in the vertebrate heart that originates during development from mesothelial precursors located in the proepicardium and septum transversum. The epicardial layer plays a key role during cardiogenesis since a subset of epicardial-derived cells (EPDCs) undergo an [...] Read more.

The epicardium is the outermost cell layer in the vertebrate heart that originates during development from mesothelial precursors located in the proepicardium and septum transversum. The epicardial layer plays a key role during cardiogenesis since a subset of epicardial-derived cells (EPDCs) undergo an epithelial–mesenchymal transition (EMT); migrate into the myocardium; and differentiate into distinct cell types, such as coronary vascular smooth muscle cells, cardiac fibroblasts, endothelial cells, and presumably a subpopulation of cardiomyocytes, thus contributing to complete heart formation. Furthermore, the epicardium is a source of paracrine factors that support cardiac growth at the last stages of cardiogenesis. Although several lineage trace studies have provided some evidence about epicardial cell fate determination, the molecular mechanisms underlying epicardial cell heterogeneity remain not fully understood. Interestingly, seminal works during the last decade have pointed out that the adult epicardium is reactivated after heart damage, re-expressing some embryonic genes and contributing to cardiac remodeling. Therefore, the epicardium has been proposed as a potential target in the treatment of cardiovascular disease. In this review, we summarize the previous knowledge regarding the regulation of epicardial cell contribution during development and the control of epicardial reactivation in cardiac repair after damage. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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31 pages, 1480 KiB

Open AccessReview

Post-Transcriptional Regulation of Molecular Determinants during Cardiogenesis

by Estefania Lozano-Velasco, Carlos Garcia-Padilla, Maria del Mar Muñoz-Gallardo, Francisco Jose Martinez-Amaro, Sheila Caño-Carrillo, Juan Manuel Castillo-Casas, Cristina Sanchez-Fernandez, Amelia E. Aranega and Diego Franco

Int. J. Mol. Sci. 2022, 23(5), 2839; https://doi.org/10.3390/ijms23052839 - 4 Mar 2022

Cited by 11 | Viewed by 4180

Abstract

Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo. The precardiac mesoderm subsequently fused at the embryonic midline constituting an embryonic linear heart tube. As development progress, the embryonic heart [...] Read more.

Cardiovascular development is initiated soon after gastrulation as bilateral precardiac mesoderm is progressively symmetrically determined at both sides of the developing embryo. The precardiac mesoderm subsequently fused at the embryonic midline constituting an embryonic linear heart tube. As development progress, the embryonic heart displays the first sign of left-right asymmetric morphology by the invariably rightward looping of the initial heart tube and prospective embryonic ventricular and atrial chambers emerged. As cardiac development progresses, the atrial and ventricular chambers enlarged and distinct left and right compartments emerge as consequence of the formation of the interatrial and interventricular septa, respectively. The last steps of cardiac morphogenesis are represented by the completion of atrial and ventricular septation, resulting in the configuration of a double circuitry with distinct systemic and pulmonary chambers, each of them with distinct inlets and outlets connections. Over the last decade, our understanding of the contribution of multiple growth factor signaling cascades such as Tgf-beta, Bmp and Wnt signaling as well as of transcriptional regulators to cardiac morphogenesis have greatly enlarged. Recently, a novel layer of complexity has emerged with the discovery of non-coding RNAs, particularly microRNAs and lncRNAs. Herein, we provide a state-of-the-art review of the contribution of non-coding RNAs during cardiac development. microRNAs and lncRNAs have been reported to functional modulate all stages of cardiac morphogenesis, spanning from lateral plate mesoderm formation to outflow tract septation, by modulating major growth factor signaling pathways as well as those transcriptional regulators involved in cardiac development. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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17 pages, 1997 KiB

Open AccessReview

Glucose-6-Phosphate Dehydrogenase, Redox Homeostasis and Embryogenesis

by Po-Hsiang Chen, Wen-Ye Tjong, Hung-Chi Yang, Hui-Ya Liu, Arnold Stern and Daniel Tsun-Yee Chiu

Int. J. Mol. Sci. 2022, 23(4), 2017; https://doi.org/10.3390/ijms23042017 - 11 Feb 2022

Cited by 10 | Viewed by 4857

Abstract

Normal embryogenesis requires complex regulation and precision, which depends on multiple mechanistic details. Defective embryogenesis can occur by various mechanisms. Maintaining redox homeostasis is of importance during embryogenesis. NADPH, as produced from the action of glucose-6-phosphate dehydrogenase (G6PD), has an important role in [...] Read more.

Normal embryogenesis requires complex regulation and precision, which depends on multiple mechanistic details. Defective embryogenesis can occur by various mechanisms. Maintaining redox homeostasis is of importance during embryogenesis. NADPH, as produced from the action of glucose-6-phosphate dehydrogenase (G6PD), has an important role in redox homeostasis, serving as a cofactor for glutathione reductase in the recycling of glutathione from oxidized glutathione and for NADPH oxidases and nitric oxide synthases in the generation of reactive oxygen (ROS) and nitrogen species (RNS). Oxidative stress differentially influences cell fate and embryogenesis. While low levels of stress (eustress) by ROS and RNS promote cell growth and differentiation, supra-physiological concentrations of ROS and RNS can lead to cell demise and embryonic lethality. G6PD-deficient cells and organisms have been used as models in embryogenesis for determining the role of redox signaling in regulating cell proliferation, differentiation and migration. Embryogenesis is also modulated by anti-oxidant enzymes, transcription factors, microRNAs, growth factors and signaling pathways, which are dependent on redox regulation. Crosstalk among transcription factors, microRNAs and redox signaling is essential for embryogenesis. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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11 pages, 715 KiB

Open AccessReview

The Insulin-like Growth Factor Signalling Pathway in Cardiac Development and Regeneration

by Sandra Díaz del Moral, Maha Benaouicha, Ramón Muñoz-Chápuli and Rita Carmona

Int. J. Mol. Sci. 2022, 23(1), 234; https://doi.org/10.3390/ijms23010234 - 26 Dec 2021

Cited by 27 | Viewed by 5595

Abstract

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport [...] Read more.

Insulin and Insulin-like growth factors (IGFs) perform key roles during embryonic development, regulating processes of cell proliferation and survival. The IGF signalling pathway comprises two IGFs (IGF1, IGF2), two IGF receptors (IGFR1, IGFR2), and six IGF binding proteins (IGFBPs) that regulate IGF transport and availability. The IGF signalling pathway is essential for cardiac development. IGF2 is the primary mitogen inducing ventricular cardiomyocyte proliferation and morphogenesis of the compact myocardial wall. Conditional deletion of the Igf1r and the insulin receptor (Insr) genes in the myocardium results in decreased cardiomyocyte proliferation and ventricular wall hypoplasia. The significance of the IGF signalling pathway during embryonic development has led to consider it as a candidate for adult cardiac repair and regeneration. In fact, paracrine IGF2 plays a key role in the transient regenerative ability of the newborn mouse heart. We aimed to review the current knowledge about the role played by the IGF signalling pathway during cardiac development and also the clinical potential of recapitulating this developmental axis in regeneration of the adult heart. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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31 pages, 7018 KiB

Open AccessHypothesis

The Midbrain Preisthmus: A Poorly Known Effect of the Isthmic Organizer

by Luis Puelles and Matias Hidalgo-Sánchez

Int. J. Mol. Sci. 2023, 24(11), 9769; https://doi.org/10.3390/ijms24119769 - 5 Jun 2023

Cited by 4 | Viewed by 1616

Abstract

This essay reexamines molecular evidence supporting the existence of the ‘preisthmus’, a caudal midbrain domain present in vertebrates (studied here in the mouse). It is thought to derive from the embryonic m2 mesomere and appears intercalated between the isthmus (caudally) and the inferior [...] Read more.

This essay reexamines molecular evidence supporting the existence of the ‘preisthmus’, a caudal midbrain domain present in vertebrates (studied here in the mouse). It is thought to derive from the embryonic m2 mesomere and appears intercalated between the isthmus (caudally) and the inferior colliculus (rostrally). Among a substantial list of gene expression mappings examined from the Allen Developing and Adult Brain Atlases, a number of quite consistent selective positive markers, plus some neatly negative markers, were followed across embryonic stages E11.5, E13.5, E15.5, E18.5, and several postnatal stages up to the adult brain. Both alar and basal subdomains of this transverse territory were explored and illustrated. It is argued that the peculiar molecular and structural profile of the preisthmus is due to its position as rostrally adjacent to the isthmic organizer, where high levels of both FGF8 and WNT1 morphogens must exist at early embryonic stages. Isthmic patterning of the midbrain is discussed in this context. Studies of the effects of the isthmic morphogens usually do not attend to the largely unknown preisthmic complex. The adult alar derivatives of the preisthmus were confirmed to comprise a specific preisthmic sector of the periaqueductal gray, an intermediate stratum represented by the classic cuneiform nucleus, and a superficial stratum containing the subbrachial nucleus. The basal derivatives, occupying a narrow retrorubral domain intercalated between the oculomotor and trochlear motor nuclei, include dopaminergic and serotonergic neurons, as well as a variety of peptidergic neuron types. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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9 pages, 266 KiB

Open AccessOpinion

Regulation of Developmental Cell Death in the Animal Kingdom: A Critical Analysis of Epigenetic versus Genetic Factors

by Juan A. Montero, Carlos Ignacio Lorda-Diez and Juan M. Hurle

Int. J. Mol. Sci. 2022, 23(3), 1154; https://doi.org/10.3390/ijms23031154 - 21 Jan 2022

Cited by 1 | Viewed by 1742

Abstract

The present paper proposes a new level of regulation of programmed cell death (PCD) in developing systems based on epigenetics. We argue against the traditional view of PCD as an altruistic “cell suicide” activated by specific gene-encoded signals with the function of favoring [...] Read more.

The present paper proposes a new level of regulation of programmed cell death (PCD) in developing systems based on epigenetics. We argue against the traditional view of PCD as an altruistic “cell suicide” activated by specific gene-encoded signals with the function of favoring the development of their neighboring progenitors to properly form embryonic organs. In contrast, we propose that signals and local tissue interactions responsible for growth and differentiation of the embryonic tissues generate domains where cells retain an epigenetic profile sensitive to DNA damage that results in its subsequent elimination in a fashion reminiscent of what happens with scaffolding at the end of the construction of a building. Canonical death genes, including Bcl-2 family members, caspases, and lysosomal proteases, would reflect the downstream molecular machinery that executes the dying process rather than being master cell death regulatory signals. Full article

(This article belongs to the Special Issue Common Molecular Mechanisms in Embryonic Development)

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