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1.
Dev Dyn ; 251(11): 1798-1815, 2022 11.
Article in English | MEDLINE | ID: mdl-35710880

ABSTRACT

BACKGROUND: The vitamin A derivative all-trans retinoic acid (RA) regulates early stages of inner ear development. As the early disruption of the RA pathway results in profound mispatterning of the developing inner ear, this confounds analyses of specific roles in later stages. Therefore, we used the temporal-specific exposure of all-trans RA or diethylaminobenzaldehyde to evaluate RA functions in late otic development. RESULTS: Perturbing late RA signaling causes behavioral defects analogous to those expected in larvae suffering from vestibular dysfunction. These larvae also demonstrate malformations of the semi-circular canals, as visualized through (a) use of the transgenic strain nkhspdmc12a, a fluorescent reporter expressed in otic epithelium; and (b) injection of the fluorescent lipophilic dye DiI. We also noted the altered expression of genes encoding ECM proteins or modifying enzymes. Other malformations of the inner ear observed in our work include the loss or reduced size of the utricular and saccular otoliths, suggesting a role for RA in otolith maintenance. CONCLUSION: Our work has identified a previously undescribed late phase of RA activity in otic development, demonstrating that vestibular defects observed in human patients in relation to perturbed RA signaling are not solely due to its early disruption in otic development.


Subject(s)
Tretinoin , Zebrafish , Animals , Humans , Zebrafish/genetics , Otolithic Membrane , Embryonic Development , Semicircular Canals , Morphogenesis
2.
Sci Rep ; 11(1): 3111, 2021 02 04.
Article in English | MEDLINE | ID: mdl-33542446

ABSTRACT

Cat eye syndrome (CES), a human genetic disorder caused by the inverted duplication of a region on chromosome 22, has been known since the late 1890s. Despite the significant impact this disorder has on affected individuals, models for CES have not been produced due to the difficulty of effectively duplicating the corresponding chromosome region in an animal model. However, the study of phenotypes associated with individual genes in this region such as CECR2 may shed light on the etiology of CES. In this study we have shown that deleterious loss of function mutations in mouse Cecr2 effectively demonstrate many of the abnormal features present in human patients with CES, including coloboma and specific skeletal, kidney and heart defects. Beyond phenotypic analyses we have demonstrated the importance of utilizing multiple genetic backgrounds to study disease models, as we see major differences in penetrance of Cecr2-related abnormal phenotype between mouse strains, reminiscent of the variability in the human syndrome. These findings suggest that Cecr2 is involved in the abnormal features of CES and that Cecr2 mice can be used as a model system to study the wide range of phenotypes present in CES.


Subject(s)
Chromosome Disorders/genetics , Coloboma/genetics , Disease Models, Animal , Eye Abnormalities/genetics , Heart Diseases/genetics , Loss of Function Mutation , Transcription Factors/genetics , Aneuploidy , Animals , Bone and Bones/metabolism , Bone and Bones/pathology , Chromosome Disorders/metabolism , Chromosome Disorders/pathology , Chromosome Duplication , Chromosomes, Human, Pair 22/chemistry , Chromosomes, Human, Pair 22/genetics , Chromosomes, Human, Pair 22/metabolism , Coloboma/metabolism , Coloboma/pathology , Embryo, Mammalian , Eye Abnormalities/metabolism , Eye Abnormalities/pathology , Female , Gene Expression , Heart Diseases/metabolism , Heart Diseases/pathology , Humans , Kidney/metabolism , Kidney/pathology , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Penetrance , Species Specificity , Transcription Factors/deficiency
3.
Article in English | MEDLINE | ID: mdl-32872284

ABSTRACT

Emerging evidence shows that homelessness continues to be a chronic public health problem throughout Canada. The Bridge Healing Program has been proposed in Edmonton, Alberta, as a novel approach to combat homelessness by using hospital emergency departments (ED) as a gateway to temporary housing. Building on the ideas of Tiny Villages, the Bridge Healing Program provides residents with immediate temporary housing before transitioning them to permanent homes. This paper aims to understand effective strategies that underlie the Tiny Villages concept by analyzing six case studies and applying the lessons learned to improving the Bridge Healing Program. After looking at six Tiny Villages, we identified four common elements of many successful Tiny Villages. These include a strong community, public support, funding with few restrictions, and affordable housing options post-graduation. The Bridge Healing Program emphasizes such key elements by having a strong team, numerous services, and connections to permanent housing. Furthermore, the Bridge Healing Program is unique in its ability to reduce repeat ED visits, lengths of stay in the ED, and healthcare costs. Overall, the Bridge Healing Program exhibits many traits associated with successful Tiny Villages and has the potential to address a gap in our current healthcare system.


Subject(s)
Housing , Ill-Housed Persons , Alberta , Canada , Costs and Cost Analysis , Humans , Program Evaluation
4.
Am J Med Genet C Semin Med Genet ; 184(3): 590-610, 2020 09.
Article in English | MEDLINE | ID: mdl-32852110

ABSTRACT

Ocular coloboma is a congenital disorder of the eye where a gap exists in the inferior retina, lens, iris, or optic nerve tissue. With a prevalence of 2-19 per 100,000 live births, coloboma, and microphthalmia, an associated ocular disorder, represent up to 10% of childhood blindness. It manifests due to the failure of choroid fissure closure during eye development, and it is a part of a spectrum of ocular disorders that include microphthalmia and anophthalmia. Use of genetic approaches from classical pedigree analyses to next generation sequencing has identified more than 40 loci that are associated with the causality of ocular coloboma. As we have expanded studies to include singleton cases, hereditability has been very challenging to prove. As such, researchers over the past 20 years, have unraveled the complex interrelationship amongst these 40 genes using vertebrate model organisms. Such research has greatly increased our understanding of eye development. These genes function to regulate initial specification of the eye field, migration of retinal precursors, patterning of the retina, neural crest cell biology, and activity of head mesoderm. This review will discuss the discovery of loci using patient data, their investigations in animal models, and the recent advances stemming from animal models that shed new light in patient diagnosis.


Subject(s)
Coloboma/genetics , Eye/growth & development , Microphthalmos/genetics , Animals , Child , Coloboma/pathology , Eye/metabolism , Humans , Microphthalmos/pathology , Neural Crest/growth & development , Neural Crest/metabolism , Organogenesis/genetics
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