Unravelling the development of the visual cortex: implications for plasticity and repair

Bourne, James A.

doi:10.1111/j.1469-7580.2010.01275.x

Cited by 51 publications

(36 citation statements)

References 205 publications

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“…In mammals, although most tissue morphogenesis is completed by birth, it has already been found that this is not the case in the CNS. Both the brain and eye continue to adapt after birth, with significant remodeling of new synaptic connections (16). Our data suggest that this postnatal plasticity might be sufficiently versatile to also allow for reversal of abnormal tissue modeling if the underlying molecular defect is corrected.…”

Section: Resultsmentioning

confidence: 82%

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Gregory‐Evans¹,

Wang²,

Wasan³

et al. 2013

J. Clin. Invest.

101

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Aniridia is a congenital and progressive panocular condition with poor visual prognosis that is associated with brain, olfactory, and pancreatic abnormalities. Development of aniridia is linked with nonsense mutations that result in paired box 6 (PAX6) haploinsufficiency. Here, we used a mouse model of aniridia to test the hypothesis that manipulation of Pax6 dosage through a mutation-independent nonsense mutation suppression strategy would limit progressive, postnatal damage in the eye. We focused on the nonsense suppression drugs 3-[5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl]benzoic acid (ataluren) and gentamicin. Remarkably, we demonstrated that nonsense suppression not only inhibited disease progression but also stably reversed corneal, lens, and retinal malformation defects and restored electrical and behavioral responses of the retina. The most successful results were achieved through topical application of the drug formulation START (0.9% sodium chloride, 1% Tween 80, 1% powdered ataluren, 1% carboxymethylcellulose), which was designed to enhance particle dispersion and to increase suspension viscosity. These observations suggest that the eye retains marked developmental plasticity into the postnatal period and remains sensitive to molecular remodeling. Furthermore, these data indicate that other neurological developmental anomalies associated with dosage-sensitive genetic mutations may be reversible through nonsense suppression therapeutics. IntroductionThe highly conserved paired box 6 (PAX6) transcription factor is pivotal to embryonic development and maintenance in the eye, brain, olfactory system, and pancreas (1). Genetic defects leading to haploinsufficiency of PAX6 cause congenital aniridia (2), a progressive panocular condition characterized by absence of iris tissue, corneal opacity, glaucoma, cataract, and foveal hypoplasia, which is also associated with brain, olfactory, and pancreatic abnormalities (3). While the genetic basis of congenital aniridia has been known for 2 decades, this has yet to be translated into preventative or corrective PAX6 treatment strategies, mainly because of PAX6 allelic heterogeneity, since more than 600 different mutations are known (4). Premature stop codons (PTCs) caused by nonsense mutations, splice-site mutations, and frameshift mutations account for 72% of all PAX6 disease-associated mutations (4); however, approximately 50% of all mutations are in-frame nonsense mutations. Therefore, we reasoned that a mutation-independent nonsense mutation suppression approach for in-frame PTCs (4) could be relevant for many patients if this could be achieved through a postnatal strategy. In this approach, during mRNA translation, a near-cognate aminoacyl tRNA is inserted into the polypeptide. Thus, as long as the PTC is not in a critical position for protein activity, then a functional protein would be produced with the potential to provide therapeutic benefit (5).We and others have previously undertaken proof-of-concept experiments showing that aminoglycosides promote readthr...

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Section: Resultsmentioning

confidence: 82%

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Gregory‐Evans¹,

Wang²,

Wasan³

et al. 2013

J. Clin. Invest.

101

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“…Injury to the cortex and to subcortical white matter tracts leads to conditions such as cerebral palsy that can involve functional reorganization of cortical areas and projections. James Bourne has described how multiple cortical visual areas develop in the primate brain (Bourne & Rosa, 2006;Burman et al 2007;Bourne, 2010 in this issue) and has shown that focal lesions in the immature brain lead to reorganization of the cortex in different ways to lesions in the adult brain, an issue that has been addressed in various model systems (Huffman et al 1999). Similarly, Janet Eyre and colleagues and Martin Staudt and colleagues have used a battery of techniques, including MRI and neurophysiological recordings in human subjects, to investigate different types of reorganization of the sensorimotor cortex and corticospinal tract in response to developmental lesions as compared with the effects of lesions in the adult (Basu et al 2010;Eyre et al 2007;Walther et al 2009;Staudt, 2010 in this issue).…”

Section: The Impact Of Imaging Techniques In Mapping Human Brain Devementioning

confidence: 99%

Renewed focus on the developing human neocortex

2010

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Many specifically human psychiatric and neurological conditions have developmental origins. Rodent models are extremely valuable for the investigation of brain development, but cannot provide insight into aspects that are specifically human. The human brain, and particularly the cerebral cortex, has some unique genetic, molecular, cellular and anatomical features, and these need to be further explored. Cortical expansion in human is not just quantitative; there are some novel types of neurons and cytoarchitectonic areas identified by their gene expression, connectivity and functions that do not exist in rodents. Recent research into human brain development has revealed more elaborated neurogenetic compartments, radial and tangential migration, transient cell layers in the subplate, and a greater diversity of early-generated neurons, including predecessor neurons. Recently there has been a renaissance of the study of human brain development because of these unique differences, made possible by the availability of new techniques. This review gives a flavour of the recent studies stemming from this renewed focus on the developing human brain.

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“…High salt intake in weanling DS rats modified cataract formation in association with hypertension [6]. In mammals, although most tissue morphogenesis is completed by birth, it has been found that the eye continues to adapt after birth [7]. Therefore, the effects on the eye of the developing organism observed with direct high salt intake might give a hint on how maternal diet could play an important role in early development during pregnancy.…”

Section: Introductionmentioning

confidence: 99%

Effects of High Salt-Exposure on the Development of Retina and Lens in 5.5-Day Chick Embryo

Chen¹,

Wang²,

Wang³

et al. 2014

Cell Physiol Biochem

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Background/Aims: Excess maternal salt intake during pregnancy may alter fetal development. However, our knowledge on how an increased salt intake during pregnancy influences fetal eye development is limited. In this study, we investigated the effects of high-salt treatment on the developing eyes in chick embryos, especially focusing on the development of the retina and the lens. Methods: 5.5-day chick embryos were exposed to 280mosm/l (n=17), or 300mosm/l (n=16) NaCl. The treated embryos were then incubated for 96 hours before they were fixed with 4% paraformaldehyde for H&E staining, whole-mount embryo immunostaining and TUNEL staining. BrdU and PH3 incorporation experiments were performed on the chick embryos after high-salt treatment. RT-PCR analyses were conducted from chick retina tissues. Results: We demonstrated that high-salt treatment altered the size of eyes in chick embryos, induced malformation of the eyes and impaired the development of the lens and the retina. We found an impaired expression of Paired box 6 (PAX6) and neuronal cells in the developing retina as revealed by neurofilament immunofluorescent staining. There was a reduction in the number of BrdU-positive cells and PH3-positive cells in the retina, indicating an impaired cell proliferation with high-salt treatment. High-salt treatment also resulted in an increased number of TUNEL-positive cells in the retina, indicating a higher amount of cell death. RT-PCR data displayed that the expression of the pro-apoptotic molecule nerve growth factor (NGF) in chick retina was increased and CyclinD1 was reduced with high-salt treatment. The size of the lens was reduced and Pax6 expression in the lens was significantly inhibited. High salt-treatment was detrimental to the migration of neural crest cells. Conclusion: Taken together, our study demonstrated that high-salt exposure of 5.5-day chick embryos led to an impairment of retina and lens development, possibly through interfering with Pax6 expression.

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Unravelling the development of the visual cortex: implications for plasticity and repair

Cited by 51 publications

References 205 publications

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Postnatal manipulation of Pax6 dosage reverses congenital tissue malformation defects

Renewed focus on the developing human neocortex

Effects of High Salt-Exposure on the Development of Retina and Lens in 5.5-Day Chick Embryo

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