Dosage requirement of Pitx2 for development of multiple organs

Development ◽  
1999 ◽  
Vol 126 (20) ◽  
pp. 4643-4651 ◽  
Author(s):  
P.J. Gage ◽  
H. Suh ◽  
S.A. Camper
Keyword(s):  
Heart Development ◽  
Threshold Level ◽  
The Body ◽  
Null Alleles ◽  
Allelic Series ◽  
Heart Tube ◽  
Rieger Syndrome ◽  
Multiple Organs ◽  
Abdominal Organs ◽  
Left Right Asymmetry

Pitx2 is a homeodomain transcription factor that is mutated in Rieger syndrome, a haploinsufficiency disorder affecting eyes and teeth. Pitx2 also has a postulated role in left-right axis determination. We assessed the requirements for Pitx2 directly by generating hypomorphic and null alleles. Heterozygotes for either allele have eye abnormalities consistent with Rieger syndrome. The ventral body wall fails to close in embryos homozygous for the null allele, leaving the heart and abdominal organs externalized and the body axis contorted. In homozygotes for either allele, the heart tube undergoes normal, rightward looping and the stomach is positioned normally. In contrast, homozygotes for both alleles exhibit right isomerization of the lungs. Thus, Pitx2 is required for left-right asymmetry of the lungs but not other organs. Homozygotes for either allele exhibit septal and valve defects, and null homozygotes have a single atrium proving that a threshold level of Pitx2 is required for normal heart development. Null homozygotes exhibit arrest of pituitary gland development at the committed Rathke pouch stage and eye defects including optic nerve coloboma and absence of ocular muscles. This allelic series establishes that Pitx2 is required for the development of mulitple organs in a dosage-sensitive manner.

Genetic basis of human left–right asymmetry disorders

2014 ◽  
Vol 16 ◽  
Author(s):  
Hao Deng ◽  
Hong Xia ◽  
Sheng Deng
Keyword(s):  
Situs Inversus ◽  
Genetic Basis ◽  
Chromosomal Abnormalities ◽  
The Body ◽  
Disease Genes ◽  
Internal Organs ◽  
Abdominal Organs ◽  
Pathogenic Genes ◽  
Left Right Asymmetry ◽  
Reduced Penetrance

Humans and other vertebrates exhibit left–right (LR) asymmetric arrangement of the internal organs, and failure to establish normal LR asymmetry leads to internal laterality disorders, includingsitus inversusandheterotaxy.Situs inversusis complete mirror-imaged arrangement of the internal organs along LR axis, whereasheterotaxyis abnormal arrangement of the internal thoraco-abdominal organs across LR axis of the body, most of which are associated with complex cardiovascular malformations. Both disorders are genetically heterogeneous with reduced penetrance, presumably because of monogenic, polygenic or multifactorial causes. Research in genetics of LR asymmetry disorders has been extremely prolific over the past 17 years, and a series of loci and disease genes involved insitus inversusandheterotaxyhave been described. The review highlights the classification, chromosomal abnormalities, pathogenic genes and the possible mechanism of human LR asymmetry disorders.

scholarly journals Getting to the Heart of Left–Right Asymmetry: Contributions from the Zebrafish Model

2021 ◽  
Vol 8 (6) ◽  
pp. 64
Author(s):  
Kelly A. Smith ◽  
Veronica Uribe
Keyword(s):  
Tube Formation ◽  
Cellular Level ◽  
The Body ◽  
Zebrafish Model ◽  
Cell Behaviour ◽  
Genetic Studies ◽  
Mortality And Morbidity ◽  
Multiple Organs ◽  
Left Right Asymmetry ◽  
Cardiac Patterning

The heart is laterally asymmetric. Not only is it positioned on the left side of the body but the organ itself is asymmetric. This patterning occurs across scales: at the organism level, through left–right axis patterning; at the organ level, where the heart itself exhibits left–right asymmetry; at the cellular level, where gene expression, deposition of matrix and proteins and cell behaviour are asymmetric; and at the molecular level, with chirality of molecules. Defective left–right patterning has dire consequences on multiple organs; however, mortality and morbidity arising from disrupted laterality is usually attributed to complex cardiac defects, bringing into focus the particulars of left–right patterning of the heart. Laterality defects impact how the heart integrates and connects with neighbouring organs, but the anatomy of the heart is also affected because of its asymmetry. Genetic studies have demonstrated that cardiac asymmetry is influenced by left–right axis patterning and yet the heart also possesses intrinsic laterality, reinforcing the patterning of this organ. These inputs into cardiac patterning are established at the very onset of left–right patterning (formation of the left–right organiser) and continue through propagation of left–right signals across animal axes, asymmetric differentiation of the cardiac fields, lateralised tube formation and asymmetric looping morphogenesis. In this review, we will discuss how left–right asymmetry is established and how that influences subsequent asymmetric development of the early embryonic heart. In keeping with the theme of this issue, we will focus on advancements made through studies using the zebrafish model and describe how its use has contributed considerable knowledge to our understanding of the patterning of the heart.

Pitx2is required at multiple stages of pituitary organogenesis: pituitary primordium formation and cell specification

Development ◽  
2002 ◽  
Vol 129 (2) ◽  
pp. 329-337 ◽  
Author(s):  
Hoonkyo Suh ◽  
Philip J. Gage ◽  
Jacques Drouin ◽  
Sally A. Camper
Keyword(s):  
Transcription Factors ◽  
Homeobox Gene ◽  
Threshold Level ◽  
Cell Types ◽  
Allelic Series ◽  
Rieger Syndrome ◽  
Rathke’S Pouch ◽  
Pituitary Development ◽  
Rathke's Pouch ◽  
Multiple Stages

Analysis of an allelic series in mice revealed that the Pitx2 homeobox gene is required at multiple stages of pituitary development. It is necessary for initiating expansion of Rathke’s pouch and maintaining expression of the fetal-specific transcription factors Hesx1 and Prop1. At later stages Pitx2 is necessary for specification and expansion of the gonadotropes and Pit1 lineage within the ventral and caudomedial anterior pituitary. Mechanistically, this is due to the dependence of several critical lineage-specific transcription factors, Pit1, Gata2, Egr1 and Sf1, on a threshold level of PITX2. The related Pitx1 gene has a role in hormone gene transcription, and it is important late in ontogeny for the final expansion of the differentiated cell types. Pitx1 and Pitx2 have overlapping functions in the expansion of Rathke’s pouch, revealing the sensitivity of pituitary organogenesis to the dosage of the PITX family. The model developed for PITX gene function in pituitary development provides a better understanding of the etiology of Rieger syndrome and may extend to other PITX-sensitive developmental processes.

scholarly journals Pseudo-dynamic analysis of heart tube formation in the mouse reveals strong regional variability and early left-right asymmetry

2021 ◽  
Author(s):  
Isaac Esteban ◽  
Patrick Schmidt ◽  
Susana Temino ◽  
Leif Kobbelt ◽  
Miguel Torres
Keyword(s):  
Heart Development ◽  
Computer Modelling ◽  
Morphological Variability ◽  
Tube Formation ◽  
Morphological Description ◽  
Heart Tube ◽  
Regional Variability ◽  
Mammalian Embryo ◽  
Morphological Variations ◽  
Left Right Asymmetry

Understanding organ morphogenesis requires a precise geometrical description of the tissues involved in the process. In highly regulative embryos, like those of mammals, morphological variability hinders the quantitative analysis of morphogenesis. In particular, the study of early heart development in mammals remains a challenging problem, due to imaging limitations and innate complexity. Around embryonic day 7.5 (E7.5), the cardiac crescent folds in an intricate and coordinated manner to produce a pumping linear heart tube at E8.25, followed by heart looping at E8.5. In this work we provide a complete morphological description of this process based on detailed imaging of a temporally dense collection of embryonic heart morphologies. We apply new approaches for morphometric staging and quantification of local morphological variations between specimens at the same stage. We identify hot spots of regionalized variability and identify left-right asymmetry in the inflow region starting at the late cardiac crescent stage, which represents the earliest signs of organ left-right asymmetry in the mammalian embryo. Finally, we generate a 3D+t digital model that provides a framework suitable for co-representation of data from different sources and for the computer modelling of the process.

ACUTE TOXICITY OF CERIUM DIOXIDE NANOPARTICLES

2019 ◽  
pp. 56-62
Author(s):  
N. V. Khodykina ◽  
L. P. Tochilkina ◽  
O. N. Novikova ◽  
M. S. Sroslov ◽  
A. Ya. Pocheptsov ◽  
...  
Keyword(s):  
Toxic Effect ◽  
Cerium Dioxide ◽  
Intraperitoneal Administration ◽  
Body Weight Loss ◽  
The Body ◽  
Prooxidant Effect ◽  
High Exposure ◽  
Abdominal Organs ◽  
Metabolic Imbalance ◽  
Hematological Changes

The resorptive effects of 0.01 M cerium nanodioxide sol upon single intraperitoneal administration to rats have been studied. The acute exposure to nanoparticles was found to have a dose-dependent general toxic effect on the body (weight loss, inflammatory changes in the abdominal organs, modification of individual behavior, hematological changes, metabolic imbalance), which develops on the background of POL activation. The prooxidant effect of cerium dioxide nanoparticles is demonstratively manifested at relatively high exposure levels (80–8 mg / kg). The threshold dose for the general toxic effect (Limch integr) is equal to 0.8 mg / kg.

scholarly journals Role of Mitochondria in Viral Infections

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 232
Author(s):  
Srikanth Elesela ◽  
Nicholas W. Lukacs
Keyword(s):  
Viral Infections ◽  
Mitochondrial Dynamics ◽  
The Body ◽  
Viral Diseases ◽  
Multiple Organs ◽  
Innate Immune Signaling ◽  
Mitochondrial Functions ◽  
Host Virus Interactions ◽  
Virus Interactions

Viral diseases account for an increasing proportion of deaths worldwide. Viruses maneuver host cell machinery in an attempt to subvert the intracellular environment favorable for their replication. The mitochondrial network is highly susceptible to physiological and environmental insults, including viral infections. Viruses affect mitochondrial functions and impact mitochondrial metabolism, and innate immune signaling. Resurgence of host-virus interactions in recent literature emphasizes the key role of mitochondria and host metabolism on viral life processes. Mitochondrial dysfunction leads to damage of mitochondria that generate toxic compounds, importantly mitochondrial DNA, inducing systemic toxicity, leading to damage of multiple organs in the body. Mitochondrial dynamics and mitophagy are essential for the maintenance of mitochondrial quality control and homeostasis. Therefore, metabolic antagonists may be essential to gain a better understanding of viral diseases and develop effective antiviral therapeutics. This review briefly discusses how viruses exploit mitochondrial dynamics for virus proliferation and induce associated diseases.

scholarly journals Molecular Characterization of Pax62Neu Through Pax610Neu: An Extension of the Pax6 Allelic Series and the Identification of Two Possible Hypomorph Alleles in the Mouse Mus musculus

Genetics ◽  
2001 ◽  
Vol 159 (4) ◽  
pp. 1689-1700
Author(s):  
Jack Favor ◽  
Heiko Peters ◽  
Thomas Hermann ◽  
Wolfgang Schmahl ◽  
Bimal Chatterjee ◽  
...  
Keyword(s):  
Amino Acid ◽  
Molecular Characterization ◽  
Amino Acid Substitution ◽  
Gene Dosage ◽  
Three Dimensional ◽  
Null Alleles ◽  
Target Sequence ◽  
Allelic Series ◽  
Phenotypic Analysis ◽  
Major Interest

Abstract Phenotype-based mutagenesis experiments will increase the mouse mutant resource, generating mutations at previously unmarked loci as well as extending the allelic series at known loci. Mapping, molecular characterization, and phenotypic analysis of nine independent Pax6 mutations of the mouse recovered in mutagenesis experiments is presented. Seven mutations result in premature termination of translation and all express phenotypes characteristic of null alleles, suggesting that Pax6 function requires all domains to be intact. Of major interest is the identification of two possible hypomorph mutations: Heterozygotes express less severe phenotypes and homozygotes develop rudimentary eyes and nasal processes and survive up to 36 hr after birth. Pax64Neu results in an amino acid substitution within the third helix of the homeodomain. Three-dimensional modeling indicates that the amino acid substitution interrupts the homeodomain recognition α-helix, which is critical for DNA binding. Whereas cooperative dimer binding of the mutant homeodomain to a paired-class DNA target sequence was eliminated, weak monomer binding was observed. Thus, a residual function of the mutated homeodomain may explain the hypomorphic nature of the Pax64Neu allele. Pax67Neu is a base pair substitution in the Kozak sequence and results in a reduced level of Pax6 translation product. The Pax64Neu and Pax67Neu alleles may be very useful for gene-dosage studies.

The physical basis of mollusk shell chiral coiling

2021 ◽  
Vol 118 (48) ◽  
pp. e2109210118
Author(s):  
Régis Chirat ◽  
Alain Goriely ◽  
Derek E. Moulton
Keyword(s):  
Mathematical Model ◽  
The Body ◽  
Symmetric Body ◽  
Model Organisms ◽  
Physical Interaction ◽  
Mechanical Forces ◽  
Hard Shell ◽  
Left Right Asymmetry ◽  
Development And Evolution ◽  
Mollusk Shell

Snails are model organisms for studying the genetic, molecular, and developmental bases of left–right asymmetry in Bilateria. However, the development of their typical helicospiral shell, present for the last 540 million years in environments as different as the abyss or our gardens, remains poorly understood. Conversely, ammonites typically have a bilaterally symmetric, planispiraly coiled shell, with only 1% of 3,000 genera displaying either a helicospiral or a meandering asymmetric shell. A comparative analysis suggests that the development of chiral shells in these mollusks is different and that, unlike snails, ammonites with asymmetric shells probably had a bilaterally symmetric body diagnostic of cephalopods. We propose a mathematical model for the growth of shells, taking into account the physical interaction during development between the soft mollusk body and its hard shell. Our model shows that a growth mismatch between the secreted shell tube and a bilaterally symmetric body in ammonites can generate mechanical forces that are balanced by a twist of the body, breaking shell symmetry. In gastropods, where a twist is intrinsic to the body, the same model predicts that helicospiral shells are the most likely shell forms. Our model explains a large diversity of forms and shows that, although molluscan shells are incrementally secreted at their opening, the path followed by the shell edge and the resulting form are partly governed by the mechanics of the body inside the shell, a perspective that explains many aspects of their development and evolution.

scholarly journals Overt Lower Gastrointestinal Bleeding and Pseudotumor: A Rare Presentation of Cytomegalovirus Infection

2017 ◽  
Vol 2017 ◽  
pp. 1-4 ◽  
Author(s):  
Akanksha Agrawal ◽  
Deepanshu Jain ◽  
Sameer Siddique
Keyword(s):  
Highly Active Antiretroviral Therapy ◽  
The Body ◽  
Cmv Infection ◽  
Rare Presentation ◽  
Multiple Organs ◽  
Highly Active ◽  
History Of ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

Cytomegalovirus (CMV) is a ubiquitous organism which can infect multiple organs of the body. In an immunocompromised patient, it can have a myriad of gastrointestinal manifestations. We report a case of recurrent hematochezia and concomitant pseudotumor in an AIDS (acquired immunodeficiency syndrome) patient attributable to CMV infection. A 62-year-old man with a history of AIDS, noncompliant with highly active antiretroviral therapy (HAART), presented with bright red blood per rectum. Index colonoscopy showed presence of multiple ulcers, colonic stenosis, and mass-like appearing lesion. Biopsy confirmed CMV infection and ruled out malignancy. Cessation of dual antiplatelet therapy and compliance with HAART lead to clinical cessation of bleeding and endoscopic healing of ulcers with complete resolution of colon mass on follow-up colonoscopy.

scholarly journals Inducible expression of human C9ORF72 36x G4C2 hexanucleotide repeats is sufficient to cause RAN translation and rapid muscular atrophy in mice

2020 ◽  
Author(s):  
F.W. Riemslagh ◽  
E.C. van der Toorn ◽  
R.F.M Verhagen ◽  
A. Maas ◽  
L.W.J. Bosman ◽  
...  
Keyword(s):  
Mouse Model ◽  
Muscular Atrophy ◽  
Time Frame ◽  
Repeat Expansion ◽  
The Body ◽  
Specific Expression ◽  
Multiple Organs ◽  
Als Patients ◽  
Flanking Regions ◽  
Ran Translation

AbstractThe hexanucleotide G4C2 repeat expansion in the first intron of the C9ORF72 gene explains the majority of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) cases. Numerous studies have indicated the toxicity of dipeptide repeats (DPRs) which are produced via repeat-associated non-AUG (RAN) translation from the repeat expansion and accumulate in the brain of C9FTD/ALS patients. Mouse models expressing the human C9ORF72 repeat and/or DPRs show variable pathological, functional and behavioral characteristics of FTD and ALS. Here, we report a new Tet-on inducible mouse model that expresses 36x pure G4C2 repeats with 100bp upstream and downstream human flanking regions. Brain specific expression causes the formation of sporadic sense DPRs aggregates upon 6 months dox induction but no apparent neurodegeneration. Expression in the rest of the body evokes abundant sense DPRs in multiple organs, leading to weight loss, neuromuscular junction disruption, myopathy and a locomotor phenotype within the time frame of four weeks. We did not observe any RNA foci or pTDP-43 pathology. Accumulation of DPRs and the myopathy phenotype could be prevented when 36x G4C2 repeat expression was stopped after 1 week. After 2 weeks of expression, the phenotype could not be reversed, even though DPR levels were reduced. In conclusion, expression of 36x pure G4C2 repeats including 100bp human flanking regions is sufficient for RAN translation of sense DPRs and evokes a functional locomotor phenotype. Our inducible mouse model highlights the importance of early diagnosis and treatment for C9FTD/ALS patients.Summary statementOnly 36 C9ORF72 repeats are sufficient for RAN translation in a new mouse model for ALS and FTD. Reducing toxic dipeptides can prevent but not reverse the phenotype.

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