scholarly journals Histology Atlas of the Developing Mouse Urinary System With Emphasis on Prenatal Days E10.5-E18.5

2019 ◽  
Vol 47 (7) ◽  
pp. 865-886 ◽  
Author(s):  
Susan A. Elmore ◽  
Sanam L. Kavari ◽  
Mark J. Hoenerhoff ◽  
Beth Mahler ◽  
Brittany E. Scott ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Initial Point ◽  
Branching Morphogenesis ◽  
Genetically Engineered ◽  
Developmental Abnormalities ◽  
Genetically Engineered Mouse Models ◽  
Stage Of Development ◽  
Hematoxylin And Eosin

Congenital abnormalities of the urinary tract are some of the most common human developmental abnormalities. Several genetically engineered mouse models have been developed to mimic these abnormalities and aim to better understand the molecular mechanisms of disease. This atlas has been developed as an aid to pathologists and other biomedical scientists for identification of abnormalities in the developing murine urinary tract by cataloguing normal structures at each stage of development. Hematoxylin and eosin- and immunohistochemical-stained sections are provided, with a focus on E10.5-E18.5, as well as a brief discussion of postnatal events in urinary tract development. A section on abnormalities in the development of the urinary tract is also provided, and molecular mechanisms are presented as supplementary material. Additionally, overviews of the 2 key processes of kidney development, branching morphogenesis and nephrogenesis, are provided to aid in the understanding of the complex organogenesis of the kidney. One of the key findings of this atlas is the histological identification of the ureteric bud at E10.5, as previous literature has provided conflicting reports on the initial point of budding. Furthermore, attention is paid to points where murine development is significantly distinct from human development, namely, in the cessation of nephrogenesis.

Spontaneous Incidental Brain Lesions in C57BL/6J Mice

2019 ◽  
Vol 57 (1) ◽  
pp. 172-182
Author(s):  
James C. Tarrant ◽  
Patrick Savickas ◽  
Lorna Omodho ◽  
Marco Spinazzi ◽  
Enrico Radaelli
Keyword(s):  
Periodic Acid ◽  
Genetically Engineered ◽  
Brain Lesions ◽  
Neuroaxonal Dystrophy ◽  
Periodic Acid Schiff ◽  
Developmental Abnormalities ◽  
Genetically Engineered Mouse Models ◽  
Biological Variables ◽  
Age Related ◽  
Human Disorders

Genetically engineered mouse lines on a C57BL/6J background are widely employed as preclinical models to study neurodegenerative human disorders and brain tumors. However, because of the lack of comprehensive data on the spontaneous background neuropathology of the C57BL/6J strain, discriminating between naturally occurring changes and lesions caused by experimental mutations can be challenging. In this context, this study aims at defining the spectrum and frequency of spontaneous brain changes in a large cohort of C57BL/6J mice and their association with specific biological variables, including age and sex. Brains from 203 experimentally naive and clinically unremarkable C57BL/6J mice were collected and analyzed by means of histopathology and immunohistochemistry. Mice ranged in age from 3 to 110 weeks with 89 females, 111 males, and 3 unknowns. Sixteen different spontaneous lesion categories were described in this cohort. Age-related neurodegenerative and/or neuroinflammatory findings represented the most common pathologic changes and included (1) Hirano-like inclusions in the thalamic neurons, (2) neuroaxonal dystrophy in the medulla oblongata, (3) periodic acid–Schiff–positive granular deposits in the neuropil of the hippocampus, and (4) progressive neuroinflammation characterized by microgliosis and astrogliosis. Neoplastic conditions, developmental abnormalities, and circulatory disorders were rarely observed incidental findings. In conclusion, this study describes spontaneous age-related brain lesions of the C57BL/6J mouse and provides a reference for evaluating and interpreting the neuropathological phenotype in genetically engineered mouse models developed and maintained on this congenic background.

scholarly journals Genetically Engineered Mouse Models Support a Major Role of Immune Checkpoint-Dependent Immunosurveillance Escape in B-Cell Lymphomas

2021 ◽  
Vol 12 ◽  
Author(s):  
Quentin Lemasson ◽  
Hussein Akil ◽  
Jean Feuillard ◽  
Christelle Vincent-Fabert
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Mouse Models ◽  
Molecular Mechanisms ◽  
Immune Escape ◽  
Genetically Engineered ◽  
Immune Checkpoints ◽  
System Control ◽  
B Cell Lymphomas ◽  
Genetically Engineered Mouse Models

These last 20 years, research on immune tumor microenvironment led to identify some critical recurrent mechanisms used in cancer to escape immune response. Through immune checkpoints, which are cell surface molecules involved in the immune system control, it is now established that tumor cells are able to shutdown the immune response. Due to the complexity and heterogeneity of Non Hodgkin B-cell Lymphomas (NHBLs), it is difficult to understand the precise mechanisms of immune escape and to explain the mitigated effect of immune checkpoints blockade for their treatment. Because genetically engineered mouse models are very reliable tools to improve our understanding of molecular mechanisms involved in B-cell transformation and, at the same time, can be useful preclinical models to predict immune response, we reviewed hereafter some of these models that highlight the immune escape mechanisms of NHBLs and open perspectives on future therapies.

scholarly journals Transcription Factor 21 Is Required for Branching Morphogenesis and Regulates the Gdnf-Axis in Kidney Development

2018 ◽  
Vol 29 (12) ◽  
pp. 2795-2808 ◽  
Author(s):  
Shintaro Ide ◽  
Gal Finer ◽  
Yoshiro Maezawa ◽  
Tuncer Onay ◽  
Tomokazu Souma ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Renal Dysplasia ◽  
Branching Morphogenesis ◽  
Mrna Levels ◽  
Metanephric Mesenchyme ◽  
Ureteric Bud ◽  
Renal Hypodysplasia ◽  
Cap Mesenchyme

BackgroundThe mammalian kidney develops through reciprocal inductive signals between the metanephric mesenchyme and ureteric bud. Transcription factor 21 (Tcf21) is highly expressed in the metanephric mesenchyme, including Six2-expressing cap mesenchyme and Foxd1-expressing stromal mesenchyme. Tcf21 knockout mice die in the perinatal period from severe renal hypodysplasia. In humans, Tcf21 mRNA levels are reduced in renal tissue from human fetuses with renal dysplasia. The molecular mechanisms underlying these renal defects are not yet known.MethodsUsing a variety of techniques to assess kidney development and gene expression, we compared the phenotypes of wild-type mice, mice with germline deletion of the Tcf21 gene, mice with stromal mesenchyme–specific Tcf21 deletion, and mice with cap mesenchyme–specific Tcf21 deletion.ResultsGermline deletion of Tcf21 leads to impaired ureteric bud branching and is accompanied by downregulated expression of Gdnf-Ret-Wnt11, a key pathway required for branching morphogenesis. Selective removal of Tcf21 from the renal stroma is also associated with attenuation of the Gdnf signaling axis and leads to a defect in ureteric bud branching, a paucity of collecting ducts, and a defect in urine concentration capacity. In contrast, deletion of Tcf21 from the cap mesenchyme leads to abnormal glomerulogenesis and massive proteinuria, but no downregulation of Gdnf-Ret-Wnt11 or obvious defect in branching.ConclusionsOur findings indicate that Tcf21 has distinct roles in the cap mesenchyme and stromal mesenchyme compartments during kidney development and suggest that Tcf21 regulates key molecular pathways required for branching morphogenesis.

Physiological and Molecular Basis of Thyroid Hormone Action

2001 ◽  
Vol 81 (3) ◽  
pp. 1097-1142 ◽  
Author(s):  
Paul M. Yen
Keyword(s):  
Thyroid Hormone ◽  
Molecular Mechanisms ◽  
Physiological Function ◽  
Nuclear Hormone Receptor ◽  
Genetically Engineered ◽  
Hormone Action ◽  
Genetically Engineered Mouse Models ◽  
Thyroid Hormone Action ◽  
Tremendous Progress ◽  
Growth Metabolism

Thyroid hormones (THs) play critical roles in the differentiation, growth, metabolism, and physiological function of virtually all tissues. TH binds to receptors that are ligand-regulatable transcription factors belonging to the nuclear hormone receptor superfamily. Tremendous progress has been made recently in our understanding of the molecular mechanisms that underlie TH action. In this review, we present the major advances in our knowledge of the molecular mechanisms of TH action and their implications for TH action in specific tissues, resistance to thyroid hormone syndrome, and genetically engineered mouse models.

scholarly journals Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Blood ◽  
2014 ◽  
Vol 124 (7) ◽  
pp. 1010-1019 ◽  
Author(s):  
Giorgia Simonetti ◽  
Maria Teresa Sabrina Bertilaccio ◽  
Paolo Ghia ◽  
Ulf Klein
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mouse Models ◽  
Human Disease ◽  
Molecular Mechanisms ◽  
Genetically Engineered ◽  
Lymphocytic Leukemia ◽  
Genetically Engineered Mouse Models ◽  
Receptor Repertoire ◽  
Human Malignancy ◽  
Species Specific

Abstract Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

scholarly journals Reciprocal Spatiotemporally Controlled Apoptosis Regulates Wolffian Duct Cloaca Fusion

2018 ◽  
Vol 29 (3) ◽  
pp. 775-783 ◽  
Author(s):  
Masato Hoshi ◽  
Antoine Reginensi ◽  
Matthew S. Joens ◽  
James A. J. Fitzpatrick ◽  
Helen McNeill ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Direct Contact ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Wolffian Duct ◽  
Systematic Analysis ◽  
Tyrosine Kinase Signaling ◽  
Metanephric Kidney ◽  
Genetic Deletion

The epithelial Wolffian duct (WD) inserts into the cloaca (primitive bladder) before metanephric kidney development, thereby establishing the initial plumbing for eventual joining of the ureters and bladder. Defects in this process cause common anomalies in the spectrum of congenital anomalies of the kidney and urinary tract (CAKUT). However, developmental, cellular, and molecular mechanisms of WD-cloaca fusion are poorly understood. Through systematic analysis of early WD tip development in mice, we discovered that a novel process of spatiotemporally regulated apoptosis in WD and cloaca was necessary for WD-cloaca fusion. Aberrant RET tyrosine kinase signaling through tyrosine (Y) 1062, to which PI3K- or ERK-activating proteins dock, or Y1015, to which PLCγ docks, has been shown to cause CAKUT-like defects. Cloacal apoptosis did not occur in RetY1062F mutants, in which WDs did not reach the cloaca, or in RetY1015F mutants, in which WD tips reached the cloaca but did not fuse. Moreover, inhibition of ERK or apoptosis prevented WD-cloaca fusion in cultures, and WD-specific genetic deletion of YAP attenuated cloacal apoptosis and WD-cloacal fusion in vivo. Thus, cloacal apoptosis requires direct contact and signals from the WD tip and is necessary for WD-cloacal fusion. These findings may explain the mechanisms of many CAKUT.

Olfactomedin-like 2A, 2B and 3 are differentially expressed in breast cancer metastases.

2019 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Genetically Engineered ◽  
Differentially Expressed ◽  
Genetically Engineered Mouse Models ◽  
Breast Cancer Metastases ◽  
Multiple Datasets ◽  
Cancer Metastases ◽  
Distant Organ ◽  
Metastatic Process ◽  
Differential Gene

Differential gene expression analysis of multiple datasets, in mice and in men revealed that transcripts of the olfactomedin-like family are differentially expressed in metastases, both in patients with breast cancer and in genetically engineered mouse models of breast cancer. The expression of olfactomedin-like genes was perturbed in metastases to the bone, brain and the lung, suggesting that these molecules function in the metastatic process rather than having tissue-specific associations with the site of dissemination. The olfactomedin-like family may play a role in the progression of breast cancer from frank tumor to colonization of distant organ sites.

scholarly journals DIPG-41. DISSECTING THE MECHANISTIC BASIS FOR ACVR1 AND PIK3CA MUTATION CO-OCCURRENCE IN DIFFUSE MIDLINE GLIOMAS USING GENETICALLY ENGINEERED MOUSE MODELS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii295-iii295
Author(s):  
Annette Wu ◽  
Tak Mak ◽  
Jerome Fortin
Keyword(s):  
Mouse Models ◽  
Pik3ca Mutation ◽  
Cell Lineage ◽  
Gene Expression Signature ◽  
Genetically Engineered ◽  
Genetically Engineered Mouse Models ◽  
Dismal Prognosis ◽  
Human Pathology ◽  
Genes Encoding ◽  
Mechanistic Basis

Abstract Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors with a dismal prognosis. Most of these tumors carry K27M mutations in histone H3-encoding genes, particularly H3F3A and HIST1H3B. In addition, activating mutations in ACVR1 and PIK3CA co-occur in a subset of DMGs. To understand how these lesions drive the development of DMGs, we generated genetically engineered mouse models in which Acvr1G328V, Hist1h3bK27M, and Pik3caH1047R are targeted to the OLIG2-expressing cell lineage. Animals carrying Acvr1G328V and Pik3caH1047R, with (“AHPO”) or without (“APO”) Hist1h3bK27M, developed high-grade diffuse gliomas involving midline and forebrain regions. Neither Acvr1G328V nor Pik3caH1047R drove tumorigenesis by themselves, but Acvr1G328V was sufficient to cause oligodendroglial differentiation arrest, pointing to a role in the earliest stages of gliomas formation. Transcriptomic analyses of AHPO and APO tumors indicated a predominantly proneural and oligodendrocyte precursor-like gene expression signature, consistent with the corresponding human pathology. Genes encoding transcription factors (TFs) with dual roles in controlling glial and neuronal differentiation were upregulated in tumors. Some of these genes were mildly induced by Acvr1G328V alone. Functional experiments using CRISPR/Cas9-mediated gene editing in patient-derived cell lines confirmed a role for some of these TFs in controlling DMG cell fitness. Overall, our results suggest that Pik3caH1047R consolidates Acvr1G328V-induced glial differentiation arrest to drive DMG development and progression.

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