Purpose: Albinism refers to a group of genetic disorders typically characterized by a loss/reduction of melanin in the hair, skin and eyes of affected patients. Apart from pigment changes, all albinism patients present with foveal hypoplasia and optic nerve misrouting, and have blurred vision. The molecular mechanisms that link this lack of pigment with neural retinal development are poorly understood, with foveal and optic tract development being difficult to model. To advance our knowledge, we developed a novel retinal organoid model of albinism, and characterized the development and outgrowth of retinal ganglion cells affected during albinism as a model for future studies. Methods: Human oculocutaneous albinism 1 (OCA1) patient‐derived stem cells were differentiated alongside controls into retinal organoids, as published previously1,2. Early retinal ganglion cells develop in the first 4 weeks of differentiation, at which point whole organoids could be plated to allow for optic nerve‐like outgrowth. Whole organoids were also fixed and analysed with immunohistochemistry (IHC) to visualize contralateral and ipsilateral ganglion cells present in the organoid. Results: IHC analysis showed differences in the number of ipsilateral and contralateral retinal ganglion cells between the healthy control and albinism organoids, in line with in vivo observations. Further, optic nerve‐like outgrowth could be achieved with both models, allowing for future research into optic nerve misrouting in albinism. Conclusions: We generated a novel retinal organoid model of oculocutaneous albinism, and characterized the retinal ganglion cell development and outgrowth. This will allow us in the future to study a different and sometimes overlooked aspect of albinism; optic nerve misrouting. References 1. Wagstaff, P. E., Ten Asbroek, A., Ten Brink, J. B., Jansonius, N. M. & Bergen, A. A. B. An alternative approach to produce versatile retinal organoids with accelerated ganglion cell development. Sci Rep 11, 1101, doi:10.1038/s41598‐020‐79651‐x (2021). 2. Ohlemacher, S. K. et al. Stepwise Differentiation of Retinal Ganglion Cells from Human Pluripotent Stem Cells Enables Analysis of Glaucomatous Neurodegeneration. Stem Cells 34, 1553–1562, doi:10.1002/stem.2356 (2016).
Tcf4 has been linked to autism, schizophrenia, and Pitt-Hopkins Syndrome (PTHS) in humans, however, the mechanisms behind its role in disease development is still elusive. In the present study, we provide evidence that Tcf4 has a critical function in the differentiation of cortical regions during development.We show that Tcf4 is present throughout the developing brain at the peak of neurogenesis. Deletion of Tcf4 results in mis-specification of the cortical layers, malformation of the corpus callosum and hypoplasia of the hippocampus. RNA-sequencing on E14.5 cortex material shows that Tcf4 functions as a transcriptional activator and loss of Tcf4 results in downregulation of genes linked to the emergence of other neurodevelopmental disorders. Taken together, we show that neurogenesis and differentiation are severely affected in Tcf4 mutants, phenocopying morphological brain defects detected in PTHS patients. The presented data identifies new leads to understand the mechanism of human brain defects and will assist in genetic counseling programs.show aberrant co-localization with SATB2. Besides these differentiation defects, the corpus callosum and both hippocampi are severely underdeveloped in these mutants. Transcriptome analyzes through RNA-sequencing on E14.5 cortical material indicate that Tcf4 is an activator of gene expression in the developing cortex and is activates genes that are linked to neurogenesis and neuronal maturation. Importantly, Tcf4 regulates genes that are known for their involvement in clinical syndromes related to PTHS and ID. Finally, the observed brain malformations phenocopy clinical features observed in PTHS patients, further establishing this mouse mutant as an excellent model for this human developmental disorder, providing mechanistic insight to the syndrome and assist in the identification of novel factors for genetic screening and genetic counseling for human patients with neurodevelopmental disorders.
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