Visual impairment in FOXG1-mutated individuals and mice

Abstract

The Forkead Box G1 (FOXG1) gene encodes for a DNA−binding transcription factor, essential for the development of the telencephalon in mammalian forebrain. Mutations in FOXG1 have been reported to be involved in the onset of Rett Syndrome, for which sequence alterations of MECP2 and CDKL5 are known. While visual alterations are not classical hallmarks of Rett syndrome, an increasing body of evidence shows visual impairment in patients and in MeCP2 and CDKL5 animal models. Herein we focused on the functional role of FOXG1 in the visual system of animal models (Foxg1+/Cre mice) and of a cohort of patients carrying FOXG1 mutations or deletions. Visual physiology of Foxg1+/Cre mice was assessed by visually evoked potentials, which revealed a significant reduction in response amplitude and visual acuity with respect to wild-type littermates. Morphological investigation showed abnormalities in the organization of excitatory/inhibitory circuits in the visual cortex. No alterations were observed in retinal structure. By examining a cohort of FOXG1-mutated patients by means of a panel of neuro-ophthalmological evaluations, we found that all of them exhibited visual alterations compatible with high level visual dysfunctions. In conclusion our data show that Foxg1 haploinsufficiency results in an impairment of mouse and patient visual function. Response to Reviewers: Pisa February 27th 2016Dear Editor, We would like to thank the referees for the thoughtful critiques on our manuscript and for the opportunity to revise our work. Please find enclosed a revised version of our manuscript (NSC-15-1232) entitled "Visual impairment in FOXG1-mutated patients and mice" by Boggio et al. As requested, we performed additional experiments on retina and visual cortex in order to more quantitavely prove the structure specific alterations and strengthen our conclusions. We included below a detailed response to the reviewer comments (in italics). References have been updated and added as suggested by referees. Sincerely, Tommaso PizzorussoReviewer #1:Major concerns 1.The description of the morphology of the five classes of retinal neurons would benefit from a quantitative approach amenable to statistical comparisons, similar to that performed for cortical GABAergic neurons in Fig. 4.We performed the requested quantitative analysis that is now shown in fig. 4. The analysis was focussed on cells in the ganglion cell layer because this layer is known to be affected in Foxg1 null mice. No significant change in the overall number of cells, and in ganglion cells identified using the RBPMS cell type-specific antibody, was present in Foxg1 heterozygous mice 2.There are no explicit statements regarding blinding of investigators to mouse genotypes during data acquisition and analyses, the use of Power Analysis to determine sample sizes, and predetermined criteria to exclude data sets. These are all critical issues that need to be performed and explicitly reported as recommended (Landis et al. Nature 2012).We included in the methods the fol...

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“…In recent years, the visual cortex has become an important model to assess cortical processing in mouse model of neurodevelopmental disorders ( 12 , 27 , 28 ). For instance, the use of visually evoked responses has been suggested as a relatively common quantitative method to directly compare cortical function in RTT patients and mouse models carrying mecp2 mutations ( 11 , 12 ).…”

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