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The axons of retinal ganglion cells (RGCs) form the optic nerve, transmitting visual information from the eye to the brain. Damage or loss of RGCs and their axons is the leading cause of visual functional defects in traumatic injury and degenerative diseases such as glaucoma. However, there are no effective clinical treatments for nerve damage in these neurodegenerative diseases. Here, we report that LIM homeodomain transcription factor Lhx2 promotes RGC survival and axon regeneration in multiple animal models mimicking glaucoma disease. Furthermore, following N-methyl-D-aspartate (NMDA)-induced excitotoxicity damage of RGCs, Lhx2 mitigates the loss of visual signal transduction. Mechanistic analysis revealed that overexpression of Lhx2 supports axon regeneration by systematically regulating the transcription of regeneration-related genes and inhibiting transcription of Semaphorin 3C (Sema3C). Collectively, our studies identify a critical role of Lhx2 in promoting RGC survival and axon regeneration, providing a promising neural repair strategy for glaucomatous neurodegeneration., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mutations in the embryonic ectoderm development (EED) cause Weaver syndrome, but whether and how EED affects embryonic brain development remains elusive. Here, we generated a mouse model in which Eed was deleted in the forebrain to investigate the role of EED. We found that deletion of Eed decreased the number of upper-layer neurons but not deeper-layer neurons starting at E16.5. Transcriptomic and genomic occupancy analyses revealed that the epigenetic states of a group of cortical neurogenesis-related genes were altered in Eed knockout forebrains, followed by a decrease of H3K27me3 and an increase of H3K27ac marks within the promoter regions. The switching of H3K27me3 to H3K27ac modification promoted the recruitment of RNA-Pol2, thereby enhancing its expression level. The small molecule activator SAG or Ptch1 knockout for activating Hedgehog signaling can partially rescue aberrant cortical neurogenesis. Taken together, we proposed a novel EED-Gli3-Gli1 regulatory axis that is critical for embryonic brain development., Competing Interests: Conflicts of interest The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

UTX, a H3K27me3 demethylase, plays an important role in mouse brain development. However, so little is known about the function of UTX in human neural differentiation and dendritic morphology. In this study, we generated UTX-null human embryonic stem cells using CRISPR/Cas9, and differentiated them into neural progenitor cells and neurons to investigate the effects of UTX loss of function on human neural development. The results showed that the number of differentiated neurons significantly reduced after loss of UTX, and that the dendritic morphology of UTX KO neurons tended to be simplified. The electrophysiological recordings showed that most of the UTX KO neurons were immature. Finally, RNA sequencing identified dozens of differentially expressed genes involved in neural differentiation and synaptic function in UTX KO neurons and our results demonstrated that UTX regulated these critical genes by resolving bivalent promoters. In summary, we establish a reference for the important role of UTX in human neural differentiation and dendritic morphology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

EED (embryonic ectoderm development) is a core component of the Polycomb repressive complex 2 (PRC2) which catalyzes the methylation of histone H3 lysine 27 (H3K27) during the process of self-renewal, proliferation, and differentiation of embryonic stem cells. However, its function in the mammalian nervous system remains unexplored. Here, we report that loss of EED in the brain leads to postnatal lethality, impaired neuronal differentiation, and malformation of the dentate gyrus. Overexpression of Sox11, a downstream target of EED through interaction with H3K27me1, restores the neuronal differentiation capacity of EED-ablated neural stem/progenitor cells (NSPCs). Interestingly, downregulation of Cdkn2a, another downstream target of EED which is regulated in an H3K27me3-dependent manner, reverses the proliferation defect of EED-ablated NSPCs. Taken together, these findings established a critical role of EED in the development of hippocampal dentate gyrus, which might shed new light on the molecular mechanism of intellectual disability in patients with EED mutations., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

The polycomb repressive complexes 1 (PRC1) and 2 (PRC2) are two distinct polycomb group (PcG) proteins that maintain the stable silencing of specific sets of genes through chromatin modifications. Although the PRC2 component EZH2 has been known as an epigenetic regulator in promoting the proliferation of neural stem/progenitor cells (NSPCs), the regulatory network that controls this process remains largely unknown. Here we show that miR-203 is repressed by EZH2 in both embryonic and adult NSPCs. MiR-203 negatively regulates the proliferation of NSPCs. One of PRC1 components, Bmi1, is a downstream target of miR-203 in NSPCs. Conditional knockout of Ezh2 results in decreased proliferation ability of both embryonic and adult NSPCs. Meanwhile, ectopic overexpression of BMI1 rescues the proliferation defects exhibited by miR-203 overexpression or EZH2 deficiency in NSPCs. Therefore, this study provides evidence for coordinated function of the EZH2-miR-203-BMI1 regulatory axis that regulates the proliferation of NSPCs., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)