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Foxn3 is part of a transcriptional network that regulates primary cilia in the developing mouse retina [RNA-Seq]

ABSTRACT: Analysis of retinas from mice with a targeted disruption of the Foxn3 gene revealed additional displaced amacrine interneurons and additional retinal astrocytes in the inner plexiform layer and in the ganglion cell layer. The forkhead transcription factor Foxn3 is a transcriptional repressor. Numerous genes linked to cilia structure or assembly were upregulated in embryonic retinas without Foxn3, including Foxj1, a forkhead transcription factor required for motile cilia. Ectopic primary cilia were observed on bipolar and amacrine interneurons in postnatal retinas without Foxn3. CUT&RUN analysis revealed that many upregulated retinal genes were bound by the Foxn3 and Rfx3 proteins. A short hydrophobic motif shared by Foxj1, Foxn4, and Foxn3 proteins was found to be required for association with the Rfx3 protein and for transcriptional repression by Foxn3, as well as for full transcriptional activation by Foxn4 with Rfx3. AlphaFold 3 predicts an interaction between the hydrophobic motif and the Rfx3 dimerization domain. Mutations in Rfx3 at the predicted interaction site disrupted association of Rfx3 with Foxn3 or Foxn4. These results reveal a new layer of transcriptional regulation of genes required for cilia, with Foxn3 functioning as a repressor of cilia genes and limiting primary cilia formation in the developing retina.

ORGANISM(S): Mus musculus

PROVIDER: GSE306964 | GEO | 2025/09/04

REPOSITORIES: GEO

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Foxn3 is part of a transcriptional network that regulates primary cilia in the developing mouse retina [CUT & RUN]

Project description:Analysis of retinas from mice with a targeted disruption of the Foxn3 gene revealed additional displaced amacrine interneurons and additional retinal astrocytes in the inner plexiform layer and in the ganglion cell layer. The forkhead transcription factor Foxn3 is a transcriptional repressor. Numerous genes linked to cilia structure or assembly were upregulated in embryonic retinas without Foxn3, including Foxj1, a forkhead transcription factor required for motile cilia. Ectopic primary cilia were observed on bipolar and amacrine interneurons in postnatal retinas without Foxn3. CUT&RUN analysis revealed that many upregulated retinal genes were bound by the Foxn3 and Rfx3 proteins. A short hydrophobic motif shared by Foxj1, Foxn4, and Foxn3 proteins was found to be required for association with the Rfx3 protein and for transcriptional repression by Foxn3, as well as for full transcriptional activation by Foxn4 with Rfx3. AlphaFold 3 predicts an interaction between the hydrophobic motif and the Rfx3 dimerization domain. Mutations in Rfx3 at the predicted interaction site disrupted association of Rfx3 with Foxn3 or Foxn4. These results reveal a new layer of transcriptional regulation of genes required for cilia, with Foxn3 functioning as a repressor of cilia genes and limiting primary cilia formation in the developing retina.

2025-09-04 | GSE306960 | GEO

Regulation of retinal amacrine cell generation by miR-216b and Foxn3 [miRNA-seq Ptf1a]

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Transcription profiling of Xenopus epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate cells, either alone or along with FoxJ1

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Loss of Stim2 in zebrafish induces retinal gene expression cellular changes resembling glaucoma characteristics [RNA-seq]

Project description:Calcium is involved in vision processes in retina and is implicated in various pathologies including glaucoma. Rods are protected against prolonged lowering of intracellular calcium ion concentrations by Store Operated Calcium Entry (SOCE). We showed zebrafish lacking SOCE calcium sensor Stim2 had problem with vision as indicated by behavior tests, staining of retina and downregulation of genes related to light perception. In this work we aimed to understand the mechanism responsible for the vision problems in stim2 zebrafish knockout. scRNA-sequencing of neuronal origin cells from brains of 5 dpf larvae identified 27 clusters. Differently expressed genes were detected in ten clusters including amacrine and GABAergic retinal interneurons and GABAergic optic tectum cells. In five clusters the proportion of cells in stim2 KO fish versus control was significantly decreased including GABAergic diencephalon and optic tectum, and was increased in amacrine and GABAergic retinal interneurons. Transmission Electron Microscopy in stim2 KO fish revealed decrease in width of inner plexiform layer (IPL), ganglion cells and their dendrites numbers what is characteristic for glaucoma. Analysis of cell density in the inner nucleus layer, which includes amacrine cells among others, showed a significant decrease in the number of GABAergic neurons. The area of cristae in photoreceptor mitochondria was statistically lower in stim2 KO than in control retinas.

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Loss of Stim2 in zebrafish induces retinal gene expression cellular changes resembling glaucoma characteristics [scRNA-seq]

Project description:Calcium is involved in vision processes in retina and is implicated in various pathologies including glaucoma. Rods are protected against prolonged lowering of intracellular calcium ion concentrations by Store Operated Calcium Entry (SOCE). We showed zebrafish lacking SOCE calcium sensor Stim2 had problem with vision as indicated by behavior tests, staining of retina and downregulation of genes related to light perception. In this work we aimed to understand the mechanism responsible for the vision problems in stim2 zebrafish knockout. scRNA-sequencing of neuronal origin cells from brains of 5 dpf larvae identified 27 clusters. Differently expressed genes were detected in ten clusters including amacrine and GABAergic retinal interneurons and GABAergic optic tectum cells. In five clusters the proportion of cells in stim2 KO fish versus control was significantly decreased including GABAergic diencephalon and optic tectum, and was increased in amacrine and GABAergic retinal interneurons. Transmission Electron Microscopy in stim2 KO fish revealed decrease in width of inner plexiform layer (IPL), ganglion cells and their dendrites numbers what is characteristic for glaucoma. Analysis of cell density in the inner nucleus layer, which includes amacrine cells among others, showed a significant decrease in the number of GABAergic neurons.The area of cristae in photoreceptor mitochondria was statistically lower in stim2 KO than in control retinas.

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Effect of FoxJ1 on expression of cilia genes

Project description:Analysis of epithelial explants injected with the intracellular domain of Notch (ICD) to block the formation of multi-ciliate cells, either alone or along with FoxJ1. FoxJ1 misexpression leads to the induction fo ectopic cilia in Xenopus laevis epithelia. Results show which genes are affected by FoxJ1 during the induction of ectopic cilia. Ciliated cells that produce a leftward fluid flow have been proposed to mediate left-right patterning in many vertebrate embryos. These cilia combine features of primary sensory and motile cilia, but how such cilia are specified is unknown. We address this issue by analyzing the Xenopus and Zebrafish homologs of FoxJ1, a forkhead transcription factor necessary for ciliogenesis in multi-ciliate cells of the mouse. We show that the cilia that underlie left-right patterning on the Xenopus gastrocoel roof plate (GRP) and Zebrafish Kupffer’s vesicle (KV) are severely shortened or fail to form in FoxJ1 morphants. We also show that misexpressing XFoxJ1 is sufficient to induce ectopic GRP-like cilia formation in frog embryos. Microarray analysis indicates that XFoxJ1 induces the formation of cilia by upregulating the expression of motile cilia genes. These results indicate that FoxJ1 is a critical determinant in specifying cilia used in left-right patterning. Keywords: Cilia Induction

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