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Wiley Interdisciplinary Reviews.... 2012The mammalian kidney, which at maturity contains thousands of nephrons joined to a highly branched collecting duct (CD) system, is an important model system for studying... (Review)
Review
The mammalian kidney, which at maturity contains thousands of nephrons joined to a highly branched collecting duct (CD) system, is an important model system for studying the development of a complex organ. Furthermore, congenital anomalies of the kidney and urinary tract, often resulting from defects in ureteric bud branching morphogenesis, are relatively common human birth defects. Kidney development is initiated by interactions between the nephric duct and the metanephric mesenchyme, leading to the outgrowth and repeated branching of the ureteric bud epithelium, which gives rise to the entire renal CD system. Meanwhile, signals from the ureteric bud induce the mesenchyme cells to form the nephron epithelia. This review focuses on development of the CD system, with emphasis on the mouse as an experimental system. The major topics covered include the origin and development of the nephric duct, formation of the ureteric bud, branching morphogenesis of the ureteric bud, and elongation of the CDs. The signals, receptors, transcription factors, and other regulatory molecules implicated in these processes are discussed. In addition, our current knowledge of cellular behaviors that are controlled by these genes and underlie development of the collecting system is reviewed.
Topics: Animals; Epithelium; Gene Expression Regulation, Developmental; Humans; Kidney; Mesoderm; Mice; Nephrons; Organogenesis; Ureter; Urinary Tract
PubMed: 22942910
DOI: 10.1002/wdev.52 -
Development (Cambridge, England) Aug 2011The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are...
The digestive tract epithelium and its adjoining mesenchyme undergo coordinated patterning and growth during development. The signals they exchange in the process are not fully characterized but include ligands of the Hedgehog (Hh) family, which originate in the epithelium and are necessary for mesenchymal cells to expand in number and drive elongation of the developing gut tube. The Notch signaling pathway has known requirements in fetal and adult intestinal epithelial progenitors. We detected Notch pathway activity in the embryonic gut mesenchyme and used conditional knockout mice to study its function. Selective disruption of the Notch effector gene RBP-Jκ (Rbpj) in the mesenchyme caused progressive loss of subepithelial fibroblasts and abbreviated gut length, revealing an unexpected requirement in this compartment. Surprisingly, constitutive Notch activity also induced rapid mesenchymal cell loss and impaired organogenesis, probably resulting from increased cell death and suggesting the need for a delicate balance in Notch signaling. Because digestive tract anomalies in mouse embryos with excess Notch activity phenocopy the absence of Hh signaling, we postulated that endodermal Hh restrains mesenchymal Notch pathway activity. Indeed, Hh-deficient embryos showed Notch overactivity in their defective gut mesenchyme and exposure to recombinant sonic hedgehog could override Notch-induced death of cultured fetal gut mesenchymal cells. These results reveal unexpected interactions between prominent signals in gastrointestinal development and provide a coherent explanation for Hh requirements in mesenchymal cell survival and organ growth.
Topics: Animals; Cell Proliferation; Female; Gastrointestinal Tract; Gene Expression Regulation, Developmental; Hedgehog Proteins; Male; Mesoderm; Mice; Mice, Knockout; Mice, Transgenic; Receptors, Notch; Signal Transduction
PubMed: 21750033
DOI: 10.1242/dev.066233 -
Journal of Mammary Gland Biology and... Jun 2013Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in... (Review)
Review
Parathyroid Hormone related Protein (PTHrP) is a critical regulator of mammary gland morphogenesis in the mouse embryo. Loss of PTHrP, or its receptor, PTHR1, results in arrested mammary buds at day 15 of embryonic development (E15). In contrast, overexpression of PTHrP converts the ventral epidermis into hairless nipple skin. PTHrP signaling appears to be critical for mammary mesenchyme specification, which in turn maintains mammary epithelial identity, directs bud outgrowth, disrupts the male mammary rudiment and specifies the formation of the nipple. In the embryonic mammary bud, PTHrP exerts its effects on morphogenesis, in part, through epithelial-stromal crosstalk mediated by Wnt and BMP signaling. Recently, PTHLH has been identified as a strong candidate for a novel breast cancer susceptibility locus, although PTHrP's role in breast cancer has not been clearly defined. The effects of PTHrP on the growth of the embryonic mammary rudiment and its invasion into the dermis may, in turn, have connections to the role of PTHrP in breast cancer.
Topics: Animals; Female; Humans; Mammary Glands, Animal; Mammary Glands, Human; Mesoderm; Parathyroid Hormone-Related Protein
PubMed: 23640717
DOI: 10.1007/s10911-013-9283-7 -
PLoS Genetics Feb 2014The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector...
The cranial bones and dermis differentiate from mesenchyme beneath the surface ectoderm. Fate selection in cranial mesenchyme requires the canonical Wnt effector molecule β-catenin, but the relative contribution of Wnt ligand sources in this process remains unknown. Here we show Wnt ligands are expressed in cranial surface ectoderm and underlying supraorbital mesenchyme during dermal and osteoblast fate selection. Using conditional genetics, we eliminate secretion of all Wnt ligands from cranial surface ectoderm or undifferentiated mesenchyme, to uncover distinct roles for ectoderm- and mesenchyme-derived Wnts. Ectoderm Wnt ligands induce osteoblast and dermal fibroblast progenitor specification while initiating expression of a subset of mesenchymal Wnts. Mesenchyme Wnt ligands are subsequently essential during differentiation of dermal and osteoblast progenitors. Finally, ectoderm-derived Wnt ligands provide an inductive cue to the cranial mesenchyme for the fate selection of dermal fibroblast and osteoblast lineages. Thus two sources of Wnt ligands perform distinct functions during osteoblast and dermal fibroblast formation.
Topics: Animals; Cell Differentiation; Ectoderm; Gene Expression Regulation, Developmental; Ligands; Mesoderm; Mice; Osteoblasts; Signal Transduction; Skull; Stem Cells; Wnt Proteins; beta Catenin
PubMed: 24586192
DOI: 10.1371/journal.pgen.1004152 -
Genesis (New York, N.Y. : 2000) Jan 2009Interactions between adjacent epithelial and mesenchymal tissues represent a highly conserved mechanism in embryonic organogenesis. In particular, the ability of the... (Review)
Review
Interactions between adjacent epithelial and mesenchymal tissues represent a highly conserved mechanism in embryonic organogenesis. In particular, the ability of the mesenchyme to instruct cellular differentiation of the epithelium is a fundamental requirement for the morphogenesis of tubular structures such as those found in the kidneys, lungs, and the developing male reproductive system. Once the tubular structure has formed, it receives signals from the mesenchyme, which can control proliferation, patterning, and differentiation of the epithelium inside the tube. However, the epithelium is not a "silent partner" in this process, and epithelium-derived factors are often required for proper maintenance of the mesenchymal compartment. Although much emphasis has been placed on the characterization of mesenchymally-derived signals required for epithelial differentiation, it is important to note that epithelial-mesenchymal interactions are a two-way street wherein each compartment requires the presence of the other for proper tubule morphogenesis and function. In this review, we discuss epithelial-mesenchymal interactions in the processes of Wolffian duct and fetal testis cord development using the mouse as a model organism and propose inhibin beta A as a conserved mesenchyme-derived regulator in these two male-specific tubular structures.
Topics: Animals; Cell Communication; Cell Differentiation; Epithelium; Male; Mesoderm; Testis; Wolffian Ducts
PubMed: 18979542
DOI: 10.1002/dvg.20453 -
The Journal of Experimental Medicine Apr 2020Innate mechanisms in the tumor stroma play a crucial role both in the initial rejection of tumors and in cancer promotion. Here, we provide a concise overview of the... (Review)
Review
Innate mechanisms in the tumor stroma play a crucial role both in the initial rejection of tumors and in cancer promotion. Here, we provide a concise overview of the innate system in cancer and recent advances in the field, including the activation and functions of innate immune cells and the emerging innate properties and modulatory roles of the fibroblastic mesenchyme. Novel insights into the diverse identities and functions of the innate immune and mesenchymal cells in the microenvironment of tumors should lead to improved anticancer therapies.
Topics: Animals; Fibroblasts; Humans; Immunity, Innate; Mesenchymal Stem Cells; Mesoderm; Neoplasms; Tumor Microenvironment
PubMed: 32044979
DOI: 10.1084/jem.20190457 -
Developmental Dynamics : An Official... Dec 1999BMP-7 is a member of the BMP family of signaling molecules that are thought to play key roles in mediating inductive events during embryogenesis. In the present study...
BMP-7 is a member of the BMP family of signaling molecules that are thought to play key roles in mediating inductive events during embryogenesis. In the present study the possible roles of BMP-7 in mediating inductive events during the initiation phase of odontogenesis and mandibular morphogenesis were investigated. To do so, we have examined the effects of agarose beads soaked in recombinant BMP-7 on E11 mouse molar-forming mesenchyme and stage 23 chick mandibular mesenchyme, and analyzed the patterns of expression of Bmp-7 in developing mouse and chick first branchial arches. Beads releasing BMP-7 induced a translucent zone, cellular proliferation, and expression of Msx-1, Msx-2, and Bmp-4 in molar-forming mesenchyme after 24 hr. The effects of BMP-7 on molar-forming mesenchyme are similar to the effects of BMP-4 and are consistent with their overlapping patterns of expression in the thickened epithelium of the early developing tooth buds, which is suggestive of cooperative and/or redundant roles of BMPs in mediating the inductive interactions during the early stages of odontogenesis. Our studies in the developing chick mandible showed that Bmp-7 is expressed in the mandibular epithelium. In the absence of mandibular epithelium, BMP-7 beads maintained cell proliferation and Msx expression in the medial mandibular mesenchyme and were able to induce cell proliferation, cell death, and Msx expression in the lateral chick mandibular mesenchyme. The effects of BMP-7 on the expression of Msx genes in lateral chick mandibular mesenchyme, although different from the effects of lateral mandibular epithelium, are similar to the effects of epithelium from the medial region where multiple Bmps are expressed. We also showed that laterally placed BMP-7 beads induced ectopic expression of Msx genes and changes in the development of posterior skeletal elements in the maxillary and mandibular arches. However, despite its proliferative effects on mandibular mesenchyme, BMP-7 did not support the directional outgrowth of the mandible. These observations suggest that epithelial-mesenchymal interactions in the medial region of the mandibular arch regulating directional outgrowth of the mandibular mesenchyme are mediated by cooperative interactions between BMPs and other growth factors. Our observations also indicated that EGF, another growth factor implicated in mediating epithelial-mesenchymal interactions in the initiation phase of odontogenesis and morphogenesis of the developing mandible, induces an extensive translucent zone and cellular proliferation in the E11 mouse molar-forming mesenchyme and stage 23 chick mandibular mesenchyme. However, in contrast to BMPs, EGF did not induce Msx-1, Msx-2, and Bmp-4, but modulated the effects of BMPs on the expression of Msx-1 and Msx-2 in these mesenchymes. Our combined data suggest that BMP-7 is a component of the signaling network mediating epithelial-mesenchymal interactions during the initiation phase of odontogenesis and morphogenesis of the mandibular arch.
Topics: Animals; Bone Morphogenetic Protein 4; Bone Morphogenetic Protein 7; Bone Morphogenetic Proteins; Cartilage, Articular; Cell Division; Chick Embryo; DNA-Binding Proteins; Epidermal Growth Factor; Epithelium; Gene Expression Regulation, Developmental; Homeodomain Proteins; MSX1 Transcription Factor; Mandible; Mesoderm; Mice; Morphogenesis; Odontogenesis; Tooth; Transcription Factors; Transforming Growth Factor beta
PubMed: 10633853
DOI: 10.1002/(SICI)1097-0177(199912)216:4/5<320::AID-DVDY2>3.0.CO;2-H -
Cellular and Molecular Gastroenterology... 2022Mesenchymal-epithelial crosstalk (MEC) in the stomach is executed by pathways such as bone morphogenetic protein (BMP) and extracellular signal-regulated kinase (ERK)....
BACKGROUND & AIMS
Mesenchymal-epithelial crosstalk (MEC) in the stomach is executed by pathways such as bone morphogenetic protein (BMP) and extracellular signal-regulated kinase (ERK). Mis-regulation of MEC disrupts gastric homeostasis and causes tumorigenesis. Protein Kinase A (PKA) crosstalks with BMP and ERK signaling; however, PKA function(s) in stomach development and homeostasis remains undefined.
METHODS
We generated a novel Six2-CrePKAcαR (CA-PKA) mouse in which expression of constitutive-active PKAcαR was induced in gastric mesenchyme progenitors. Lineage tracing determined spatiotemporal activity of Six2-Cre in the stomach. For phenotyping CA-PKA mice histological, co-immunofluorescence, immunoblotting, mRNA sequencing, and bioinformatics analyses were performed.
RESULTS
Lineage tracing showed that Six2-Cre activity in the stomach is restricted to the mesenchymal compartment. CA-PKA mice showed disruption of gastric homeostasis characterized by aberrant mucosal development and epithelial hyperproliferation; ultimately developing multiple features of gastric corpus preneoplasia including decreased parietal cells, mucous cell hyperplasia, spasmolytic peptide expressing metaplasia with intestinal characteristics, and dysplastic and invasive cystic glands. Furthermore, mutant corpus showed marked chronic inflammation characterized by infiltration of lymphocytes and myeloid-derived suppressor cells along with the upregulation of innate and adaptive immune system components. Striking upregulation of inflammatory mediators and STAT3 activation was observed. Mechanistically, we determined there is an activation of ERK1/2 and downregulation of BMP/SMAD signaling characterized by marked upregulation of BMP inhibitor gremlin 1.
CONCLUSIONS
We report a novel role of PKA signaling in gastric MEC execution and show that PKA activation in the gastric mesenchyme drives preneoplasia by creating a proinflammatory and proproliferative microenvironment associated with the downregulation of BMP/SMAD signaling and activation of ERK1/2.
Topics: Animals; Bone Morphogenetic Proteins; Cyclic AMP-Dependent Protein Kinases; Gastric Mucosa; Mesoderm; Mice; Stomach
PubMed: 35690337
DOI: 10.1016/j.jcmgh.2022.06.001 -
Anatomical Record (Hoboken, N.J. : 2007) Dec 2009Common pathological features of neurodegenerative diseases are progressive dysfunction and neuronal death. In amyotrophic lateral sclerosis (ALS), motor neurons are... (Review)
Review
Common pathological features of neurodegenerative diseases are progressive dysfunction and neuronal death. In amyotrophic lateral sclerosis (ALS), motor neurons are selectively affected, leading to death because of paralysis. The main therapeutic goal in neurodegenerative diseases is to diminish neural dysfunction and to replace non-functional cells with the new ones. "Cell-oriented" treatment strategies include isolation of neural stem cells (NSC), their controlled differentiation, and cellular injections targeting the affected region. Beneficial effects of injected cells result from the combination of cell replacement and secretion of the growth factors. Here, we summarize the current state of isolation and differentiation of NSC, and emphasize the embryo tail bud as a particular region where neuroepithelium differentiates from undifferentiated mesenchymal cells over the course of normal development. The possibility to obtain cells from autologous mesenchyme capable of integrating into affected regions represents a major challenge whose achievement should circumvent the pitfall of the immune reaction against transplanted cells. We also present our own results: when intravenously injected in symptomatic ALS rats, NSC migrated to the motor cortex and continued to differentiate. Thus, we illustrate that the use of NSC in rodent models of ALS may represent a paradigm for other neurodegenerative diseases.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Culture Techniques; Cell Differentiation; Cell Separation; Graft Survival; Humans; Mesoderm; Neurogenesis; Rats; Stem Cell Transplantation; Stem Cells; Transplantation, Autologous
PubMed: 19943351
DOI: 10.1002/ar.20971 -
Cell Adhesion & Migration 2009Epithelial to mesenchymal transition (EMT) is a morphogenetic process in which cells lose their epithelial characteristics and gain mesenchymal properties, and is... (Review)
Review
Epithelial to mesenchymal transition (EMT) is a morphogenetic process in which cells lose their epithelial characteristics and gain mesenchymal properties, and is fundamental for many tissue remodeling events in developmental and pathological conditions. Although general cell biology of EMT has been well-described, how it is executed in diverse biological settings depends largely on individual context, and as a consequence, regulatory points for each EMT may vary. Here we discuss developmental and cellular events involved in chick gastrulation EMT. Regulated disruption of epithelial cell/basement membrane (BM) interaction is a critical early step. This takes place after molecular specification of mesoderm cell fate, but before the disruption of tight junctions. The epithelial cell/BM interaction is mediated by small GTPase RhoA and through the regulation of basal microtubule dynamics. We propose that EMT is not regulated as a single morphogenetic event. Components of EMT in different settings may share similar regulatory mechanisms, but the sequence of their execution and critical regulatory points vary for each EMT.
Topics: Animals; Cell Lineage; Chick Embryo; Epithelial Cells; Mesoderm
PubMed: 19262172
DOI: 10.4161/cam.3.2.7373