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Molecular recording of mammalian embryogenesis
Nature. 2019 Jun;570(7759):77-82. doi: 10.1038/s41586-019-1184-5. Epub 2019 May 13.
Chan MM1,2, Smith ZD3,4,5, Grosswendt S6, Kretzmer H6, Norman TM1,2, Adamson B1,2,7, Jost M1,2,8, Quinn JJ1,2, Yang D1,2, Jones MG1,2,9, Khodaverdian A10,11, Yosef N10,11,12,13, Meissner A14,15,16, Weissman JS17,18.
Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes. PMID: 31086336 DOI: 10.1038/s41586-019-1184-5
Histology Atlas of the Developing Prenatal and Postnatal Mouse Central Nervous System, with Emphasis on Prenatal Days E7.5 to E18.5
Toxicol Pathol. 2017 Aug;45(6):705-744. doi: 10.1177/0192623317728134. Epub 2017 Sep 11.
Chen VS1,2, Morrison JP3,2, Southwell MF4, Foley JF5, Bolon B6, Elmore SA4.
Evaluation of the central nervous system (CNS) in the developing mouse presents unique challenges, given the complexity of ontogenesis, marked structural reorganization over very short distances in 3 dimensions each hour, and numerous developmental events susceptible to genetic and environmental influences. Developmental defects affecting the brain and spinal cord arise frequently both in utero and perinatally as spontaneous events, following teratogen exposure, and as sequelae to induced mutations and thus are a common factor in embryonic and perinatal lethality in many mouse models. Knowledge of normal organ and cellular architecture and differentiation throughout the mouse's life span is crucial to identify and characterize neurodevelopmental lesions. By providing a well-illustrated overview summarizing major events of normal in utero and perinatal mouse CNS development with examples of common developmental abnormalities, this annotated, color atlas can be used to identify normal structure and histology when phenotyping genetically engineered mice and will enhance efforts to describe and interpret brain and spinal cord malformations as causes of mouse embryonic and perinatal lethal phenotypes. The schematics and images in this atlas illustrate major developmental events during gestation from embryonic day (E)7.5 to E18.5 and after birth from postnatal day (P)1 to P21. KEYWORDS: CNS atlas; brain; development; embryo; genetically engineered mice; neonate; spinal cord PMID: 28891434 PMCID: PMC5754028 DOI: 10.1177/0192623317728134
Making the Mouse Blastocyst: Past, Present, and Future
Curr Top Dev Biol. 2016;117:275-88. doi: 10.1016/bs.ctdb.2015.11.015. Epub 2016 Feb 12.
The study of the preimplantation mouse embryo has progressed over the past 50 years from descriptive biology through experimental embryology to molecular biology and genetics. Along the way, the molecular pathways that lead to the establishment of the three cell lineages of the blastocyst have become more clearly understood but the fundamental questions of lineage commitment remain the same as those laid out in early studies. With new tools of genome manipulation, in vivo imaging and single-cell analysis, the mouse blastocyst is an excellent model system to understand how organized cell fate decisions are made in a self-organizing developmental context. © 2016 Elsevier Inc. All rights reserved. KEYWORDS: Blastocyst; Cell lineage; Chimera; FGF signaling; Hippo signaling; Mouse; Pluripotency; Polarity
Morphological maturation of the mouse brain: An in vivo MRI and histology investigation
Neuroimage. 2016 Jan 15;125:144-52. doi: 10.1016/j.neuroimage.2015.10.009. Epub 2015 Oct 14.
Hammelrath L1, Škokić S2, Khmelinskii A3, Hess A4, van der Knaap N5, Staring M6, Lelieveldt BP7, Wiedermann D8, Hoehn M9. Author information Abstract With the wide access to studies of selected gene expressions in transgenic animals, mice have become the dominant species as cerebral disease models. Many of these studies are performed on animals of not more than eight weeks, declared as adult animals. Based on the earlier reports that full brain maturation requires at least three months in rats, there is a clear need to discern the corresponding minimal animal age to provide an "adult brain" in mice in order to avoid modulation of disease progression/therapy studies by ongoing developmental changes. For this purpose, we have studied anatomical brain alterations of mice during their first six months of age. Using T2-weighted and diffusion-weighted MRI, structural and volume changes of the brain were identified and compared with histological analysis of myelination. Mouse brain volume was found to be almost stable already at three weeks, but cortex thickness kept decreasing continuously with maximal changes during the first three months. Myelination is still increasing between three and six months, although most dramatic changes are over by three months. While our results emphasize that mice should be at least three months old when adult animals are needed for brain studies, preferred choice of one particular metric for future investigation goals will result in somewhat varying age windows of stabilization. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. KEYWORDS: Brain development; Cortex; DTI; MRI; Mouse brain; Myelination PMID 26458518
Histology Atlas of the Developing Mouse Hepatobiliary Hemolymphatic Vascular System with Emphasis on Embryonic Days 11.5-18.5 and Early Postnatal Development
Toxicol Pathol. 2016 Mar 8. pii: 0192623316630836. [Epub ahead of print]
Swartley OM1, Foley JF2, Livingston DP 3rd3, Cullen JM1, Elmore SA4.
A critical event in embryo development is the proper formation of the vascular system, of which the hepatobiliary system plays a pivotal role. This has led researchers to use transgenic mice to identify the critical steps involved in developmental disorders associated with the hepatobiliary vascular system. Vascular development is dependent upon normal vasculogenesis, angiogenesis, and the transformation of vessels into their adult counterparts. Any alteration in vascular development has the potential to cause deformities or embryonic death. Numerous publications describe specific stages of vascular development relating to various organs, but a single resource detailing the stage-by-stage development of the vasculature pertaining to the hepatobiliary system has not been available. This comprehensive histology atlas provides hematoxylin & eosin and immunohistochemical-stained sections of the developing mouse blood and lymphatic vasculature with emphasis on the hepatobiliary system between embryonic days (E) 11.5-18.5 and the early postnatal period. Additionally, this atlas includes a 3-dimensional video representation of the E18.5 mouse venous vasculature. One of the most noteworthy findings of this atlas is the identification of the portal sinus within the mouse, which has been erroneously misinterpreted as the ductus venosus in previous publications. Although the primary purpose of this atlas is to identify normal hepatobiliary vascular development, potential embryonic abnormalities are also described. © The Author(s) 2016. KEYWORDS: atlas; embryo; hepatobiliary development; lymphatic development; mouse; portal sinus; vascular development PMID 26961180
Fluorescence-based visualization of autophagic activity predicts mouse embryo viability
Sci Rep. 2014 Mar 31;4:4533. doi: 10.1038/srep04533.
Tsukamoto S1, Hara T2, Yamamoto A3, Kito S1, Minami N4, Kubota T5, Sato K6, Kokubo T1.
Abstract Embryo quality is a critical parameter in assisted reproductive technologies. Although embryo quality can be evaluated morphologically, embryo morphology does not correlate perfectly with embryo viability. To improve this, it is important to understand which molecular mechanisms are involved in embryo quality control. Autophagy is an evolutionarily conserved catabolic process in which cytoplasmic materials sequestered by autophagosomes are degraded in lysosomes. We previously demonstrated that autophagy is highly activated after fertilization and is essential for further embryonic development. Here, we developed a simple fluorescence-based method for visualizing autophagic activity in live mouse embryos. Our method is based on imaging of the fluorescence intensity of GFP-LC3, a versatile marker for autophagy, which is microinjected into the embryos. Using this method, we show that embryonic autophagic activity declines with advancing maternal age, probably due to a decline in the activity of lysosomal hydrolases. We also demonstrate that embryonic autophagic activity is associated with the developmental viability of the embryo. Our results suggest that embryonic autophagic activity can be utilized as a novel indicator of embryo quality. PMID 24681842
4D imaging reveals a shift in chromosome segregation dynamics during mouse pre-implantation development
Cell Cycle. 2012 Dec 19;12(1). [Epub ahead of print]
Yamagata K, Fitzharris G. Source Research Institute for Microbial Diseases; Osaka University; Suita, Osaka Japan.
Cells of the early developing mammalian embryo frequently mis-segregate chromosomes during cell division, causing daughter cells to inherit an erroneous numbers of chromosomes. Why the embryo is so susceptible to errors is unknown, and the mechanisms that embryos employ to accomplish chromosome segregation are poorly understood. Chromosome segregation is performed by the spindle, a fusiform-shaped microtubule-based transient organelle. Here we present a detailed analysis of 4D fluorescence-confocal data sets of live embryos progressing from the one-cell embryo stage through to blastocyst in vitro, providing some of the first mechanistic insights into chromosome segregation in the mammalian embryo. We show that chromosome segregation occurs as a combined result of poleward chromosome motion (anaphase-A) and spindle elongation (anaphase-B), which occur simultaneously at the time of cell division. Unexpectedly, however, regulation of the two anaphase mechanisms changes significantly between the first and second embryonic mitoses. In one-cell embryos, the velocity of anaphase-A chromosome motion and the velocity and overall extent of anaphase-B spindle elongation are significantly constrained compared with later stages. As a result, chromosomes are delivered close to the center of the forming two-cell stage blastomeres at the end of the first mitosis. In subsequent divisions, anaphase-B spindle elongation is faster and more extensive, resulting in the delivery of chromosomes to the distal plasma membrane of the newly forming blastomeres. Metaphase spindle length scales with cell size from the two-cell stage onwards, but is substantially shorter in the first mitosis than in the second mitosis, and the duration of mitosis-1 is substantially greater than subsequent divisions. Thus, there is a striking and unexpected shift in the approach to cell division between the first and second mitotic divisions, which likely reflects adaptations to the unique environment within the developing embryo.
Application of in utero electroporation and live imaging in the analyses of neuronal migration during mouse brain development
Med Mol Morphol. 2012 Dec;45(1):1-6. Epub 2012 Mar 20.
Nishimura YV, Shinoda T, Inaguma Y, Ito H, Nagata K. Source Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi, 480-0392, Japan.
Correct neuronal migration is crucial for brain architecture and function. During cerebral cortex development (corticogenesis), excitatory neurons generated in the proliferative zone of the dorsal telencephalon (mainly ventricular zone) move through the intermediate zone and migrate past the neurons previously located in the cortical plate and come to rest just beneath the marginal zone. The in utero electroporation technique is a powerful method for rapid gain- and loss-of-function studies of neuronal development, especially neuronal migration. This method enabled us to introduce genes of interest into ventricular zone progenitor cells of mouse embryos and to observe resulting phenotypes such as proliferation, migration, and cell morphology at later stages. In this Award Lecture Review, we focus on the application of the in utero electroporation method to functional analyses of cytoskeleton-related protein septin. We then refer to, as an advanced technique, the in utero electroporation-based real-time imaging method for analyses of cell signaling regulating neuronal migration. The in utero electroporation method and its application would contribute to medical molecular morphology through identification and characterization of the signaling pathways disorganized in various neurological and psychiatric disorders.
Cell fate decisions and axis determination in the early mouse embryo
Development. 2012 Jan;139(1):3-14.
Takaoka K, Hamada H. Source Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, 1-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
The mouse embryo generates multiple cell lineages, as well as its future body axes in the early phase of its development. The early cell fate decisions lead to the generation of three lineages in the pre-implantation embryo: the epiblast, the primitive endoderm and the trophectoderm. Shortly after implantation, the anterior-posterior axis is firmly established. Recent studies have provided a better understanding of how the earliest cell fate decisions are regulated in the pre-implantation embryo, and how and when the body axes are established in the pregastrulation embryo. In this review, we address the timing of the first cell fate decisions and of the establishment of embryonic polarity, and we ask how far back one can trace their origins.
Development of the pulmonary vein and the systemic venous sinus: an interactive 3D overview
PLoS One. 2011;6(7):e22055. doi: 10.1371/journal.pone.0022055. Epub 2011 Jul 11.
van den Berg G1, Moorman AF.
Knowledge of the normal formation of the heart is crucial for the understanding of cardiac pathologies and congenital malformations. The understanding of early cardiac development, however, is complicated because it is inseparably associated with other developmental processes such as embryonic folding, formation of the coelomic cavity, and vascular development. Because of this, it is necessary to integrate morphological and experimental analyses. Morphological insights, however, are limited by the difficulty in communication of complex 3D-processes. Most controversies, in consequence, result from differences in interpretation, rather than observation. An example of such a continuing debate is the development of the pulmonary vein and the systemic venous sinus, or "sinus venosus". To facilitate understanding, we present a 3D study of the developing venous pole in the chicken embryo, showing our results in a novel interactive fashion, which permits the reader to form an independent opinion. We clarify how the pulmonary vein separates from a greater vascular plexus within the splanchnic mesoderm. The systemic venous sinus, in contrast, develops at the junction between the splanchnic and somatic mesoderm. We discuss our model with respect to normal formation of the heart, congenital cardiac malformations, and the phylogeny of the venous tributaries.
A conditional knockout resource for the genome-wide study of mouse gene function
Nature. 2011 Jun 15;474(7351):337-42. doi: 10.1038/nature10163.
Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A. Source Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK. firstname.lastname@example.org
Gene targeting in embryonic stem cells has become the principal technology for manipulation of the mouse genome, offering unrivalled accuracy in allele design and access to conditional mutagenesis. To bring these advantages to the wider research community, large-scale mouse knockout programmes are producing a permanent resource of targeted mutations in all protein-coding genes. Here we report the establishment of a high-throughput gene-targeting pipeline for the generation of reporter-tagged, conditional alleles. Computational allele design, 96-well modular vector construction and high-efficiency gene-targeting strategies have been combined to mutate genes on an unprecedented scale. So far, more than 12,000 vectors and 9,000 conditional targeted alleles have been produced in highly germline-competent C57BL/6N embryonic stem cells. High-throughput genome engineering highlighted by this study is broadly applicable to rat and human stem cells and provides a foundation for future genome-wide efforts aimed at deciphering the function of all genes encoded by the mammalian genome.
PMID: 21677750 http://www.ncbi.nlm.nih.gov/pubmed/21677750
A high-resolution anatomical atlas of the transcriptome in the mouse embryo
PLoS Biol. 2011 Jan 18;9(1):e1000582.
Diez-Roux G, Banfi S, Sultan M, Geffers L, Anand S, Rozado D, Magen A, Canidio E, Pagani M, Peluso I, Lin-Marq N, Koch M, Bilio M, Cantiello I, Verde R, De Masi C, Bianchi SA, Cicchini J, Perroud E, Mehmeti S, Dagand E, Schrinner S, Nürnberger A, Schmidt K, Metz K, Zwingmann C, Brieske N, Springer C, Hernandez AM, Herzog S, Grabbe F, Sieverding C, Fischer B, Schrader K, Brockmeyer M, Dettmer S, Helbig C, Alunni V, Battaini MA, Mura C, Henrichsen CN, Garcia-Lopez R, Echevarria D, Puelles E, Garcia-Calero E, Kruse S, Uhr M, Kauck C, Feng G, Milyaev N, Ong CK, Kumar L, Lam M, Semple CA, Gyenesei A, Mundlos S, Radelof U, Lehrach H, Sarmientos P, Reymond A, Davidson DR, Dollé P, Antonarakis SE, Yaspo ML, Martinez S, Baldock RA, Eichele G, Ballabio A.
Telethon Institute of Genetics and Medicine, Naples, Italy.
Ascertaining when and where genes are expressed is of crucial importance to understanding or predicting the physiological role of genes and proteins and how they interact to form the complex networks that underlie organ development and function. It is, therefore, crucial to determine on a genome-wide level, the spatio-temporal gene expression profiles at cellular resolution. This information is provided by colorimetric RNA in situ hybridization that can elucidate expression of genes in their native context and does so at cellular resolution. We generated what is to our knowledge the first genome-wide transcriptome atlas by RNA in situ hybridization of an entire mammalian organism, the developing mouse at embryonic day 14.5. This digital transcriptome atlas, the Eurexpress atlas (http://www.eurexpress.org), consists of a searchable database of annotated images that can be interactively viewed. We generated anatomy-based expression profiles for over 18,000 coding genes and over 400 microRNAs. We identified 1,002 tissue-specific genes that are a source of novel tissue-specific markers for 37 different anatomical structures. The quality and the resolution of the data revealed novel molecular domains for several developing structures, such as the telencephalon, a novel organization for the hypothalamus, and insight on the Wnt network involved in renal epithelial differentiation during kidney development. The digital transcriptome atlas is a powerful resource to determine co-expression of genes, to identify cell populations and lineages, and to identify functional associations between genes relevant to development and disease.
PMID: 21267068 http://www.ncbi.nlm.nih.gov/pubmed/21267068
Eurexpress transcriptome atlas http://www.eurexpress.org
Making the blastocyst: lessons from the mouse
J Clin Invest. 2010 Apr;120(4):995-1003. doi: 10.1172/JCI41229. Epub 2010 Apr 1.
Cockburn K, Rossant J. Source Department of Molecular Genetics, University of Toronto, Canada.
Mammalian preimplantation development, which is the period extending from fertilization to implantation, results in the formation of a blastocyst with three distinct cell lineages. Only one of these lineages, the epiblast, contributes to the embryo itself, while the other two lineages, the trophectoderm and the primitive endoderm, become extra-embryonic tissues. Significant gains have been made in our understanding of the major events of mouse preimplantation development, and recent discoveries have shed new light on the establishment of the three blastocyst lineages. What is less clear, however, is how closely human preimplantation development mimics that in the mouse. A greater understanding of the similarities and differences between mouse and human preimplantation development has implications for improving assisted reproductive technologies and for deriving human embryonic stem cells.
Prenatal behavior of the C57BL/6J mouse: a promising model for human fetal movement during early to mid-gestation
Dev Psychobiol. 2009 Jan;51(1):84-94. doi: 10.1002/dev.20348.
Kleven GA1, Ronca AE.
The study of fetal neurobehavioral development in genetically altered mice promises a significant advance in our understanding of the prenatal origins of developmental disabilities in humans. Despite their importance, little is known about fetal neurobehavioral development in mice. In this study, we observed prenatal behavioral patterns of the C57BL/6J mouse, a common background strain for genetically altered mice, and report their similarity to those observed in the early to mid-gestation human fetus. Fetal offspring from pregnant C57BL/6J dams were observed on the day before birth (E18 of a 19-day gestation). Scoring and analysis of fetal movement included Prechtl's Method for Qualitative Assessment, Interlimb Movement Synchrony, a measure of the temporal relationship between movements of limb pairs, and Behavioral State, quantified through detailed analysis of high and low amplitude limb movements. With the exception of fetal breathing movements, all categories and patterns of behavior typically reported in the early to mid-gestation human fetus were observed in the C57BL/6J mouse fetus. Our results suggest that behavioral analysis of fetal C57BL/6J mice may yield important new insights into early to mid-gestation human behavioral development. PMID: 18980217 PMCID: PMC4315139 DOI: 10.1002/dev.20348
Developmental alveolarization of the mouse lung.
Dev Dyn. 2008 Aug;237(8):2108-16.
Mund SI, Stampanoni M, Schittny JC.
Institute of Anatomy, University of Bern, Switzerland.
Abstract Postnatal lung development is not well characterized in mice, especially the time point when alveolarization is completed. Using the total length and the length density of the free septal edge as measured for the formation of new septa, we followed alveolarization throughout postnatal lung development (days 2-125). Furthermore, the alveolar surface area was estimated. The formation of new septa was observed until day 36. Approximately 10% of the septa present in adult mice were formed prenatally by branching morphogenesis, approximately 50% were generated postnatally before and approximately 40% after maturation of the alveolar microvasculature. Approximately 5% of the alveolar surface area present during adulthood was present before alveolarization started, approximately 55% was formed during alveolarization (days 4-36) and approximately 40% afterward due to growth processes. We conclude that alveolarization continues until young adulthood and that the maturation of the alveolar microvasculature does not preclude further alveolarization.
In vivo quantification of embryonic and placental growth during gestation in mice using micro-ultrasound
Mu J, Slevin JC, Qu D, McCormick S, Adamson SL. Reprod Biol Endocrinol. 2008 Aug 12;6:34. PMID: 18700008
- "RESULTS: Gestational sac dimension provided the earliest measure of conceptus size. Sac dimension derived using regression analysis increased from 0.84 mm at E7.5 to 6.44 mm at E11.5 when it was discontinued. The earliest measurement of embryo size was crown-rump length (CRL) which increased from 1.88 mm at E8.5 to 16.22 mm at E16.5 after which it exceeded the field of view. From E10.5 to E18.5 (full term), progressive increases were observed in embryonic biparietal diameter (BPD) (0.79 mm to 7.55 mm at E18.5), abdominal circumference (AC) (4.91 mm to 26.56 mm), and eye lens diameter (0.20 mm to 0.93 mm). Ossified femur length was measureable from E15.5 (1.06 mm) and increased linearly to 2.23 mm at E18.5. In contrast, placental diameter (PD) and placental thickness (PT) increased from E10.5 to E14.5 then remained constant to term in accord with placental weight. Ultrasound and light microscopy measurements agreed with no significant bias and a discrepancy of less than 25%. Regression equations predicting gestational age from individual variables, and embryonic weight (BW) from CRL, BPD, and AC were obtained. The prediction equation BW = -0.757 + 0.0453 (CRL) + 0.0334 (AC) derived from CD-1 data predicted embryonic weights at E17.5 in three other strains of mice with a mean discrepancy of less than 16%. "
Synaptogenesis in the mouse olfactory bulb during glomerulus development
Eur J Neurosci. 2008 Jun;27(11):2838-46.
Blanchart A, Romaguera M, García-Verdugo JM, de Carlos JA, López-Mascaraque L.
Department of Cellular, Molecular and Developmental Neurobiology, Instituto Cajal, CSIC, Madrid, Spain.
Synaptogenesis is essential for the development of neuronal networks in the brain. In the olfactory bulb (OB) glomeruli, numerous synapses must form between sensory olfactory neurons and the dendrites of mitral/tufted and periglomerular cells. Glomeruli develop from E13 to E16 in the mouse, coincident with an increment of the neuropil in the border between the external plexiform (EPL) and olfactory nerve layers (ONL), coupled to an extensive labelling of phalloidin and GAP-43 from the ONL to EPL. We have tracked synaptogenesis in the OB during this period by electron microscopy (EM) and immunolabelling of the transmembrane synaptic vesicle glycoprotein SV-2. No SV-2 labelling or synapses were detected at E13, although electrodense junctions lacking synaptic vesicles could be observed by EM. At E14, sparse SV-2 labelling appears in the most ventral and medial part of the incipient OB, which displays a ventro-dorsal gradient by E15 but covers the entire OB by E16. These data establish a spatio-temporal pattern of synaptogenesis, which perfectly matches with the glomeruli formation in developing OB.
Doppler ultrasound in mice
Echocardiography. 2007 Jan;24(1):97-112.
Department of Cardiology and Angiology, Hospital of the University of Münster, Germany. email@example.com Abstract Color, power, spectral, and tissue Doppler have been applied to mice. Due to the noninvasive nature of the technique, serial intraindividual Doppler measurements of cardiovascular function are feasible in wild-type and genetically altered mice before and after microsurgical procedures or to follow age-related changes. Fifty-megahertz ultrasound biomicroscopy allows to record the first beats of the embryonic mouse heart at somite stage 5, and the first Doppler-flow signals can be recorded after the onset of intrauterine cardiovascular function at somite stage 7. Using 10- to 20-MHz ultrasound transducers in the mouse embryo, cardiac, and circulatory function can be studied as early as 7.5 days after postcoital mucous plug. Postnatal Doppler ultrasound examinations in mice are possible from birth to senescent age. Several strain-, age-, and gender-related differences of Doppler ultrasound findings have been reported in mice. Results of Doppler examinations are influenced by the experimental settings as stress testing or different forms of anesthesia. This review summarizes the present status of Doppler ultrasound examinations in mice and animal handling in the framework of a comprehensive phenotype characterization of cardiac contractile and circulatory function.
Molecular models for murine sperm-egg binding
J Biol Chem. 2006 May 19;281(20):13853-6. Epub 2006 Feb 1. Clark GF, Dell A.
Department of Obstetrics, Gynecology and Women's Health, Division of Reproductive and Perinatal Research, School of Medicine, University of Missouri, Columbia, Missouri 65202, USA. firstname.lastname@example.org Abstract Murine sperm initiate fertilization by binding to the specialized extracellular matrix of mouse eggs, known as the zona pellucida. Over the past decade, powerful genetic, biophysical, and biochemical techniques have been employed to gain new insights into this interaction. Evidence from these studies does not support either of two major models for binding first proposed over two decades ago. Two more recently established models suggest that protein-protein interactions predominate during this initial stage of fertilization. Another model proposes that about 75-80% of the murine sperm bound to zona pellucida under well defined in vitro conditions is carbohydrate dependent, with the remaining sperm bound via protein-protein interactions. Mounting evidence suggests that the carbohydrate sequences coating the murine egg could be employed as specific immune recognition markers. Continued investigation of this system may resolve many of these controversial findings and reveal novel functions for murine zona pellucida glycoproteins.
The postnatal development of the hypothalamic-pituitary-adrenal axis in the mouse
Int J Dev Neurosci. 2003 May;21(3):125-32.
Schmidt MV, Enthoven L, van der Mark M, Levine S, de Kloet ER, Oitzl MS. Source Gorlaeus Laboratories, Division of Medical Pharmacology, Leiden/Amsterdam Center for Drug Research, Leiden University Medical Centre, Leiden University, P.O. Box 9502, The Netherlands. email@example.com Erratum in Int J Dev Neurosci. 2006 Jun;24(4):293. Schmidt, M [corrected to Schmidt, Mathias V].
The main characteristic of the postnatal development of the stress system in the rat is the so-called stress hypo-responsive period (SHRP). Lasting from postnatal day (pnd) 4 to pnd 14, this period is characterized by very low basal corticosterone levels and an inability of mild stressors to induce an enhanced ACTH and corticosterone release. During the last years, the mouse has become a generally used animal in stress research, also due to the wide availability of genetically modified mouse strains. However, very few data are available on the ontogeny of the stress system in the mouse. This study therefore describes the postnatal ontogeny of peripheral and central aspects of the hypothalamic-pituitary-adrenal (HPA) axis in the mouse. We measured ACTH and corticosterone in blood and CRH, urocortin 3 (UCN3), mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) transcripts in the brain at postnatal days 1, 2, 4, 6, 9, 12, 14 and 16. Our results show that we can subdivide the postnatal development of the HPA axis in the mouse in two phases. The first phase corresponds to the SHRP in the rat and lasts from right after birth (pnd 1) until pnd 12. Basal corticosterone levels were low and novelty exposure did not enhance corticosterone or ACTH levels. This period is further characterized by a high expression of CRH in the paraventricular nucleus (PVN) of the hypothalamus. Expression levels of GR in the hippocampus and UCN3 in the perifornical area are low at birth but increase significantly during the SHRP, both reaching the highest expression level at pnd 12. In the second phase, the mice have developed past the SHRP and were now exhibiting enhanced corticosterone basal levels and a response of ACTH and corticosterone to mild novelty stress. CRH expression was decreased significantly, while expression of UCN3 and GR remained high, with a small decrease at pnd 16. The expression of MR in the hippocampus was very dynamic throughout the postnatal development of the HPA axis and changed in a time and subregion specific manner. These results demonstrate for the first time the correlation between the postnatal endocrine development of the mouse and gene expression changes of central regulators of HPA axis function.
mouse oocyte survival
- Intact fetal ovarian cord formation promotes mouse oocyte survival and development http://www.ncbi.nlm.nih.gov/pubmed/20064216 | http://www.biomedcentral.com/1471-213X/10/2
- "Taste tissue development in mice starts around embryonic day (E) 11.5, after the emergence of the tongue swelling on the floor of developing mandible (8, 9). This is followed by formation of the taste placode (E12.5), gustatory papillae (E13.5), and taste buds (around birth)"
Development of the heart: (3) formation of the ventricular outflow tracts, arterial valves, and intrapericardial arterial trunks
Heart. 2003 Sep;89(9):1110-8.
Anderson RH, Webb S, Brown NA, Lamers W, Moorman A.
Interactions between trophoblast cells and the maternal and fetal circulation in the mouse placenta
Dev Biol. 2002 Oct 15;250(2):358-73.
Adamson SL1, Lu Y, Whiteley KJ, Holmyard D, Hemberger M, Pfarrer C, Cross JC.
Abstract Mammalian embryos have an intimate relationship with their mothers, particularly with the placental vasculature from which embryos obtain nutrients essential for growth. It is an interesting vascular bed because maternal vessel number and diameter change dramatically during gestation and, in rodents and primates, the terminal blood space becomes lined by placental trophoblast cells rather than endothelial cells. Molecular genetic studies in mice aimed at identifying potential regulators of these processes have been hampered by lack of understanding of the anatomy of the vascular spaces in the placenta and the general nature of maternal-fetal vascular interactions. To address this problem, we examined the anatomy of the mouse placenta by preparing plastic vascular casts and serial histological sections of implantation sites from embryonic day (E) 10.5 to term. We found that each radial artery carrying maternal blood into the uterus branched into 5-10 dilated spiral arteries located within the metrial triangle, populated by uterine natural killer (uNK) cells, and the decidua basalis. The endothelial-lined spiral arteries converged together at the trophoblast giant cell layer and emptied into a few straight, trophoblast-lined "canals" that carried maternal blood to the base of the placenta. Maternal blood then percolated back through the intervillous space of the labyrinth toward the maternal side of the placenta in a direction that is countercurrent to the direction of the fetal capillary blood flow. Trophoblast cells were found invading the uterus in two patterns. Large cells that expressed the trophoblast giant cell-specific gene Plf (encoding Proliferin) invaded during the early postimplantation period in a pattern tightly associated with spiral arteries. These peri/endovascular trophoblast were detected only approximately 150-300 microm upstream of the main giant cell layer. A second type of widespread interstitial invasion in the decidua basalis by glycogen trophoblast cells was detected after E12.5. These cells did not express Plf, but rather expressed the spongiotrophoblast-specific gene Tpbp. Dilation of the spiral arteries was obvious between E10.5 and E14.5 and was associated with a lack of elastic lamina and smooth muscle cells. These features were apparent even in the metrial triangle, a site far away from the invading trophoblast cells. By contrast, the transition from endothelium-lined artery to trophoblast-lined (hemochorial) blood space was associated with trophoblast giant cells. Moreover, the shaping of the maternal blood spaces within the labyrinth was dependent on chorioallantoic morphogenesis and therefore disrupted in Gcm1 mutants. These studies provide important insights into how the fetoplacental unit interacts with the maternal intrauterine vascular system during pregnancy in mice. PMID 12376109
Neurulation in the mouse. I. The ontogenesis of neural segments and the determination of topographical regions in a central nervous system
Sakai Y. Anat Rec. 1987 Aug;218(4):450-7.PMID: 3662046
- "Ontogenesis of neural segments and positional relationships between the segments and other organs during neurulation were studied in 1,423 ICR mouse embryos by binocular dissecting, light, and scanning electron microscopy. Late in the presomite stage, two transverse sulci, preotic and otic, were seen on the prospective luminal surface of the neural folds. By somite stage 19, the former subdivided into five neuromeres, and by somite stage 21, the latter subdivided into four neuromeres. From the rostral, preotic sulcus, moreover, five other neuromeres were formed by somite stage 20, and between the otic sulcus and the first somite, two neuromeres were formed by somite stage 28. In the caudal part, from the level of the first somite, a total of 39 neuromeres were formed one after another by somite stage 39, and their positions almost correlated with each corresponding somite. Furthermore, the isthmus grew in the boundary between the fifth and sixth neuromere. The most protruding zone in the preotic sulcus formed the eighth neuromere and was located adjacent to the first branchial arch and the trigeminal ganglion. The most protruding zone in the otic sulcus also formed the 11th neuromere and was located adjacent to the second branchial arch. The 12th and 13th neuromeres were situated adjacent to the otic vesicle; the 23rd to 28th neuromeres, adjacent to the forelimb bud; and the 40th to 46th neuromeres, adjacent to the hindlimb bud."
The histogenetic potential of neural plate cells of early-somite-stage mouse embryos
Chan WY, Tam PP. J Embryol Exp Morphol. 1986 Jul;96:183-93.PMID: 3805982
- "Postnatal fast muscle fibre type growth is divided into distinct phases in mouse xtensor digitorum longus (EDL): myofibre hypertrophy is initially supported by a rapid increase in the number of myonuclei, but nuclear addition stops around P21. Since the significant myofibre hypertrophy from P21 to adulthood occurs without the net addition of new myonuclei, a considerable expansion of the myonuclear domain results. Satellite cell numbers are initially stable, but then decrease to reach the adult level by P21. Thus the adult number of both myonuclei and satellite cells is already established by three weeks of postnatal growth in mouse." (EDL fast type II fibres in adult)
- Mouse models of congenital cardiovascular disease. Moon A. Curr Top Dev Biol. 2008;84:171-248. Review. PMID: 19186245
- Mouse models for investigating the developmental basis of human birth defects. Moon AM. Pediatr Res. 2006 Jun;59(6):749-55. Epub 2006 Apr 26. PMID: 16641221
- http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18083227 murine placenta contains two invasive cell types, trophoblast giant cells (TGC) and glycogen trophoblast cells (GlyT) TGC population is now recognized to have several subtypes, two of which are invasive; TGCs that form a barrier between the maternal decidua and the underlying placenta (parietal TGCs) and TGCs that invade via an endovascular route (spiral artery-associated TGCs)
A 4D atlas and morphologic database
<pubmed>18713865</pubmed>| PMC2527911 | PNAS "This work makes magnetic resonance microscopy of the mouse embryo and neonate broadly available with carefully annotated normative data and an extensive environment for collaborations."
Mouse Lung Stage Ages
mouse lung development can be divided into 5 stages:
- Embryonic Stage (E9 to E11.5), in which lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs
- Pseudoglandular Stage (E11.5 to E16.5), in which conducting epithelial tubes surrounded by thick mesenchyme are formed, distinguished by extensive airway branching
- Canalicular stage (E16.5 to E17.5), in which bronchioles are produced, characterized by an increasing number of capillaries in close contact with cuboidal epithelium and the beginning of alveolar epithelium development
- Saccular Stage (E17.5 to PN5), in which alveolar ducts and air sacs are developed
- Alveolar Stage (PN5 to PN28), in which secondary septation occurs, defined by a marked increase of the number and size of capillaries and alveoli
|Embryonic||E9 to E11.5||lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs|
|Pseudoglandular||E11.5 to E16.5||conducting epithelial tubes surrounded by thick mesenchyme are formed, extensive airway branching|
|Canalicular||E16.5 to E17.5||bronchioles are produced, increasing number of capillaries in close contact with cuboidal epithelium and the beginning of alveolar epithelium development|
|Saccular||E17.5 to PN5||alveolar ducts and air sacs are developed|
|Alveolar||PN5 to PN28||secondary septation occurs, marked increase of the number and size of capillaries and alveoli|
Human + Mouse
|Embryonic||week 4 to 5||E9 to E11.5||lung buds originate as an outgrowth from the ventral wall of the foregut where lobar division occurs|
|Pseudoglandular||week 5 to 17||E11.5 to E16.5||conducting epithelial tubes surrounded by thick mesenchyme are formed, extensive airway branching|
|Canalicular||week 16 to 25||E16.5 to E17.5||bronchioles are produced, increasing number of capillaries in close contact with cuboidal epithelium and the beginning of alveolar epithelium development|
|Saccular||week 24 to 40||E17.5 to PN5||alveolar ducts and air sacs are developed|
|Alveolar||late fetal to 8 years||PN5 to PN28||secondary septation occurs, marked increase of the number and size of capillaries and alveoli|
Mouse Rat Comparison
Anatomical and Biological Date for the Mouse, Mus musculus, and Rat, Rattus norvegicus
Weight 20-40 grams 300-4-- grams Adult male 25-90 grams 250-300 grams female Birth 1.5 grams 5-6 grams Life span 2 years - max. 2-3 years - Max 4 years Breeding age 3 yr. 2 mo. and weight male 60 days - 20-35 100 days - 300 grams
female 50-60 days - 100 days - 200 grams
Estrus cycle 4-5 days 5 days Gestation 17-21 days - 20-23 days - Avg. 21
with lactation Add 3-5 days Add 5-7 days Litter size 1-23 - Avg. 10-12 8-17 - Avg. 10 Number of 6-10 8-12 litters Weaning age and weight 16-20 days - 21 days - 40-50 grams
Postpartum yes yes heart Breeding life male 18 months 12-14 months female 10-12 months, 6-10 1 year - 4-5 litters
Mating pair yes yes colony 1 male to 3 females 1 male to 3-4 females Water 1.5 cc/10 G. body wt. 1 cc/10 G.body wt.
Ad libitum Ad libitum
Feed usage 4-5 grams/day 12-15 grams/day Dry food consumption by young begins 10 days Approx. 12 days Hair growth 2-3 days 3-5 days apparent Recommended 72 F 70-80 F temperature Humidity 45-55 45-55 Light Minimal 14 2 hours Noise Minimal Minimal Heart beat adult 600 (328-780)min 328(261-600)min newborn ----- 161(81-241)min Breathing rate 163(84-230)min 94(75-115)min Body 97.5 F.(36.5C.) 99.1F.(37.3C) temperature Hematology RBC/mm 9 x 10 6 7-10x106 Avg.9.35x106 WBC/mm 8 - 16 x 103 6 - 18x103 Avg.9x103 Differential Lymphocytes 70# 78# Neutrophils 20# 20# Monocytes 10# <1% Ecsinophils <1% 2#
Old External Links
Many no longer functioning (2001)
- Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory)
- The e-Mouse Atlas Project EMAP
Mouse Gene Expression
- EMAGE is a database of in situ gene expression data in the mouse embryo and an accompanying suite of tools to search and analyse the data. (All site content, except where otherwise noted, is licensed under a Creative Commons Attribution License.)
- Eurexpress transcriptome atlas a High-Resolution Anatomical Atlas of the Transcriptome in the Mouse Embryo.
- GenePaint.org is a digital atlas of gene expression patterns in the mouse.
- Mouse Imaging Centre
- NCBI- Mouse Genome Sequencing
- Mouse Genome Informatics
- EBI- Mouse Genome Sequencing
- ANEX Rat and Mouse Database - (University of Tokushima)
- Genetic and Physical Maps of the Mouse Genome (Whitehead Institute/MIT)
- Genetic Location Database (University of Southampton)
- Koop Human and Mouse Genome Project Research (University of Victoria)
- Genome Systems, Inc.
Mouse Jackson Laboratory
- Jackson Laboratory
- Jackson Laboratory Induced Mutant Resource
- Jackson Laboratory BioInformatics Electronic Bulletin Board System
- Mouse Inbred Strains (Jackson Labs)
- Mouse Linkage Map
- Mouse Nomenclature Rules and Guidelines (Jackson Labs)
- Helicobacter hepaticus, a Recently Recognized Bacterial Pathogen, Associated with Chronic Hepatitis and Hepatocellular Neoplasia in Laboratory Mice (CDC)
- Helicobacter Infection in Laboratory Mice: History, Significance, Detection and Management (Charles River)
- Infectious Diseases of Mice and Rats (NAS-ILAR)
- Infectious Diseases of Mice and Rats Companion Guide (NAS-ILAR)
- Infectious Diseases of Mice and Rats (AFIP-POLA)
- Murine Helicobacters (NCI)
- Archives of Transgenic-List
- Mammary Transgene Database (Baylor College of Medicine)
- Targeted Mutagenesis in Mice: A Video Guide
- TBASE - Transgenic/Targeted Mutation Database
- B Universal Ltd.
- BIG BLUE (Big Blue Transgenic Mouse Mailing List Archives)
- Big Blue lacI Transgenic Mouse Page
- Charles River Laboratories, Inc.
- Chrysalis DNX Transgenic Services
Mouse Transgenic Facilities
- Transgenic Animal Facility (University of Connecticut Biotechnology Center)
- Transgenic Animal Facility (University of Illinois Biotechnology Center)
- Transgenic Animal Facility (University of Iowa)
- Transgenic Animal Facility (Karolinska Institute)
- Transgenic Animal Facility (University of Western Australia)
- Transgenic Animal Facility (University of Wisconsin Biotechnology Center)
- Transgenic Animal Model Core (University of Michigan)
- Transgenic Core (Baylor College of Medicine SPORE)
- Transgenic Facility (University of Colorado Health Science Center)
- Transgenic Facility (University of Kentucky)
- Transgenic & Knockout Mouse Facility (University of Maryland at Baltimore)
- Transgenic-List Archives
- Transgenic Models of Skin Disease Core (Harvard Skin Disease Research Center)
- Transgenic Mouse Core Facilities (Mount Sinai School of Medicine)
- Transgenic Mouse Core Facility (University of Virginia)
- Transgenic Mouse Facility (Columbia-Presbyterian Cancer Center)
- Transgenic Mouse Facility (Duke Comprehensive Cancer Center)
- Transgenic Mouse Facility (SUNY-Stony Brook)
- Transgenic Mouse Facility (University of California-Irvine)
- Transgenic Mouse Facility (University of South Carolina)
- GenitoUrinary Development Molecular Anatomy Project (GUDMAP) Renal Development Tutorial | Genital Development Tutorial
Mouse Unsorted Links
- Covance Research Products
- Edison Biotechnology Institute (Ohio University)
- Encyclopedia of the Mouse Genome (Jackson Laboratory)
- EUCIB Mouse Backcross Database (MBx)
- Harlan Sprague Dawley, Inc.
- It's a Knockout
- Jackson Laboratory Gopher Server
- Lane List of Named Mutations and Polymorphic Loci
- Lexicon Genetics, Inc.
- Lymphocytic Choriomeningitis Virus: An Unrecognized Teratogenic Pathogen (CDC)
- M & B Breeding and Research Centre Ltd.
- Map Manager Software
- Mice and Men: Making the Most of Our Similarities (ORNL)
- Microinjection Workshop
- Mouse Atlas and Gene Expression Database Project
- Mouse Cytogenetic Map Image
- Mouse Idiograms
- Mouse Linkage Map
- Mouse and Rat Research Home Page
- MouseUp HyperCard Transgenic Mouse Database (Macintosh)
- MRC Mouse Genome Centre
- National Institute of Genetics Mouse Genetic Resources (Japan)
- NIH Animal Genetic Resource
- NIH Directory of Transgenic Mice
- NIH Mouse Club
- Of Mice and Men (HHMI's Blazing a Genetic Trail)
- Online Mendelian Inheritance in Animals (University of Sydney)
- Pathology of Genetically-altered Mice
- Portable Dictionary of the Mouse Genome
- Review of Pasteurella pneumotropica (Charles River)
- The Mouse in Science: Cancer Research
- The Mouse in Science: Monoclonal Antibodies
- The Mouse in Science: Vaccines
- The Mouse in Science: Why Mice?