Phenotypic Analysis of a New Mouse Model for Genetic Deafness: “Hush Puppy”

2003 ◽  
Vol 104 (s49) ◽  
pp. 66P-66P
Author(s):  
Henry Pau ◽  
Helmut Fuchs ◽  
Martin Hrabe de Angelis ◽  
Karen P. Steel
Keyword(s):  
Mouse Model ◽  
Phenotypic Analysis ◽  
Genetic Deafness

OTD/OTX2 functional equivalence depends on 5′ and 3′ UTR-mediated control ofOtx2mRNA for nucleo-cytoplasmic export and epiblast-restricted translation

Development ◽  
2001 ◽  
Vol 128 (23) ◽  
pp. 4801-4813 ◽  
Author(s):  
Dario Acampora ◽  
Pietro Pilo Boyl ◽  
Massimo Signore ◽  
Juan Pedro Martinez-Barbera ◽  
Cristina Ilengo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transcriptional Control ◽  
Mrna Translation ◽  
Regulatory Control ◽  
Functional Equivalence ◽  
Control Mechanisms ◽  
Phenotypic Analysis ◽  
A Cell ◽  
Anterior Patterning

How gene activity is translated into phenotype and how it can modify morphogenetic pathways is of central importance when studying the evolution of regulatory control mechanisms. Previous studies in mouse have suggested that, despite the homeodomain-restricted homology, Drosophila orthodenticle (otd) and murine Otx1 genes share functional equivalence and that translation of Otx2 mRNA in epiblast and neuroectoderm might require a cell type-specific post-transcriptional control depending on its 5′ and 3′ untranslated sequences (UTRs).In order to study whether OTD is functionally equivalent to OTX2 and whether synthesis of OTD in epiblast is molecularly dependent on the post-transcriptional control of Otx2 mRNA, we generated a first mouse model (otd2) in which an Otx2 region including 213 bp of the 5′ UTR, exons, introns and the 3′ UTR was replaced by an otd cDNA and a second mutant (otd2FL) replacing only exons and introns of Otx2 with the otd coding sequence fused to intact 5′ and 3′ UTRs of Otx2.otd2 and otd2FL mRNAs were properly transcribed under the Otx2 transcriptional control, but mRNA translation in epiblast and neuroectoderm occurred only in otd2FL mutants. Phenotypic analysis revealed that visceral endoderm (VE)-restricted translation of otd2 mRNA was sufficient to rescue Otx2 requirement for early anterior patterning and proper gastrulation but it failed to maintain forebrain and midbrain identity.Importantly, epiblast and neuroectoderm translation of otd2FL mRNA rescued maintenance of anterior patterning as it did in a third mouse model replacing, as in otd2FL, exons and introns of Otx2 with an Otx2 cDNA (Otx22c). The molecular analysis has revealed that Otx2 5′ and 3′ UTR sequences, deleted in the otd2 mRNA, are required for nucleo-cytoplasmic export and epiblast-restricted translation. Indeed, these molecular impairments were completely rescued in otd2FL and Otx22c mutants. These data provide novel in vivo evidence supporting the concept that during evolution pre-existing gene functions have been recruited into new developmental pathways by modifying their regulatory control.

scholarly journals Reducing Aspergillus fumigatus Virulence through Targeted Dysregulation of the Conidiation Pathway

mBio ◽  
2020 ◽  
Vol 11 (1) ◽  
Author(s):  
James I. P. Stewart ◽  
Vinicius M. Fava ◽  
Joshua D. Kerkaert ◽  
Adithya S. Subramanian ◽  
Fabrice N. Gravelat ◽  
...  
Keyword(s):  
Mouse Model ◽  
Aspergillus Fumigatus ◽  
Vegetative Growth ◽  
Wall Structure ◽  
Invasive Infection ◽  
Phenotypic Analysis ◽  
Airborne Spores ◽  
Content Type

ABSTRACT Inhalation of conidia of the opportunistic mold Aspergillus fumigatus by immunocompromised hosts can lead to invasive pulmonary disease. Inhaled conidia that escape immune defenses germinate to form filamentous hyphae that invade lung tissues. Conidiation rarely occurs during invasive infection of the human host, allowing the bulk of fungal energy to be directed toward vegetative growth. We hypothesized that forced induction of conidiation during infection can suppress A. fumigatus vegetative growth, impairing the ability of this organism to cause disease. To study the effects of conidiation pathway dysregulation on A. fumigatus virulence, a key transcriptional regulator of conidiation (brlA) was expressed under the control of a doxycycline-inducible promoter. Time- and dose-dependent brlA overexpression was observed in response to doxycycline both in vitro and in vivo. Exposure of the inducible brlA overexpression strain to low doses of doxycycline under vegetative growth conditions in vitro induced conidiation, whereas high doses arrested growth. Overexpression of brlA attenuated A. fumigatus virulence in both an invertebrate and mouse model of invasive aspergillosis. RNA sequencing studies and phenotypic analysis revealed that brlA overexpression results in altered cell signaling, amino acid, and carbohydrate metabolism, including a marked upregulation of trehalose biosynthesis and a downregulation in the biosynthesis of the polysaccharide virulence factor galactosaminogalactan. This proof of concept study demonstrates that activation of the conidiation pathway in A. fumigatus can reduce virulence and suggests that brlA-inducing small molecules may hold promise as a new class of therapeutics for A. fumigatus infection. IMPORTANCE The mold Aspergillus fumigatus reproduces by the production of airborne spores (conidia), a process termed conidiation. In immunocompromised individuals, inhaled A. fumigatus conidia can germinate and form filaments that penetrate and damage lung tissues; however, conidiation does not occur during invasive infection. In this study, we demonstrate that forced activation of conidiation in filaments of A. fumigatus can arrest their growth and impair the ability of this fungus to cause disease in both an insect and a mouse model of invasive infection. Activation of conidiation was linked to profound changes in A. fumigatus metabolism, including a shift away from the synthesis of polysaccharides required for cell wall structure and virulence in favor of carbohydrates used for energy storage and stress resistance. Collectively, these findings suggest that activation of the conidiation pathway may be a promising approach for the development of new agents to prevent or treat A. fumigatus infection.

Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

1987 ◽  
Vol 45 ◽  
pp. 726-727
Author(s):  
H. D. Geissinge ◽  
L.D. Rhodes
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Tibialis Anterior ◽  
Physiological Activity ◽  
Mdx Mice ◽  
Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

Mouse model of gastric infection with cytotoxin-expressing strain of Helicobacter pylori in studying of pathogenesis of chronic gastric ulcer

1998 ◽  
Vol 13 (11-s4) ◽  
pp. S178-S184 ◽  
Author(s):  
PETER KONTUREK ◽  
TOMASZ BRZOZOWSKI ◽  
STANISLAW KONTUREK ◽  
ELZBIETA KARCZEWSKA ◽  
ROBERT PAJDO ◽  
...  
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Ulcer ◽  
Mouse Model ◽  
Chronic Gastric Ulcer
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