The Role of Hippo Signaling Pathway in the Development of the Nervous System

Li, Xifan; Li, Kaixuan; Chen, Yu; Fang, Fang

doi:10.1159/000515633

Cited by 13 publications

(6 citation statements)

References 86 publications

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“…Strikingly, all those conditions caused by NUP205 mutations are related with YAP/TAZ expression. [61][62][63][64][65][66][67][68] In conclusion, our findings highlight the important role of YAP/TAZ signaling in podocyte homeostasis by connecting the shuttling of YAP and TAZ to a nucleoporin, known to cause which highlights new specific therapeutic targets for FSGS like stabilizing nuclear YAP activity in podocytes.…”

Section: Discussionmentioning

confidence: 59%

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

Ester

Cabrita

Ventzke

et al. 2023

Preprint

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Background: Mutations in genes encoding nuclear pore proteins (NUPs) cause steroid-resistant nephrotic syndrome (SRNS) and focal and segmental glomerulosclerosis (FSGS). The mechanisms of how NUP deficiency may cause podocyte dysfunction and failure of the kidney filtration barrier are elusive. The tightly controlled activity of the transcriptional effectors of the evolutionarily conserved Hippo pathway YAP and TAZ is essential for podocyte homeostasis. Here we analyze the role of NUPs in controlling YAP/TAZ nuclear import and activity in podocytes. Methods: We used quantitative label-free mass spectrometry to characterize the YAP/TAZ interactomes in podocytes, particularly identifying NUP interactions. Moreover, we specifically studied NUP205 in controlling YAP/TAZ nuclear import and YAP/TAZ-dependent target gene expression. Results: Here we identify the disease-causing nuclear pore proteins NUP107, NUP133, NUP205, and XPO5 as components of YAP and TAZ protein complexes in podocytes. We demonstrate that NUP205 is essential for YAP/TAZ nuclear import. The nuclear interaction of YAP/TAZ with TEAD1 and their transcriptional activity were dependent on NUP205 expression. Furthermore, we identify a feedback regulatory mechanism that controls YAP activity depending on TAZ-mediated NUP205 expression. Conclusion: This study links the disease protein NUP205 with the activity of the transcriptional regulators and Hippo effectors YAP and TAZ and suggests a pathogenic role of YAP/TAZ-deregulation in podocytes in patients with NUP205 mutations. Moreover, this study suggests an important role of YAP/TAZ signaling in human FSGS.

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Section: Discussionmentioning

confidence: 59%

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

Ester

Cabrita

Ventzke

et al. 2023

Preprint

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“…Our analysis revealed that Gm10545, Gm16096, Gm29260, and Mir100 hg were involved in mannose-type O -glycan biosynthesis, providing a mechanism by which m 6 A-methylated DElncRNAs affected the development of NTDs. Moreover, A730017L22Rik, Gm19265, and Gm5165 were implicated in the Hippo signaling pathway, which has established roles in neuronal cell differentiation, neuroinflammation, and neuronal death ( Cheng et al, 2020 ; Li X. et al, 2021 ). The Hippo/YAP signaling pathway has been implicated in the development of neurological diseases ( Bao et al, 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Identifying key m6A-methylated lncRNAs and genes associated with neural tube defects via integrative MeRIP and RNA sequencing analyses

Yang

Zhang

et al. 2022

Front. Genet.

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Objective: N6-methyladenosine (m6A) is a common post-transcriptional modification of messenger RNAs (mRNAs) and long non-coding RNAs (lncRNAs). However, m6A-modified lncRNAs are still largely unexplored. This study aimed to investigate differentially m6A-modified lncRNAs and genes involved in neural tube defect (NTD) development.Methods: Pregnant Kunming mice (9–10 weeks of age) were treated with retinoic acid to construct NTD models. m6A levels and methyltransferase-like 3 (METTL3) expression were evaluated in brain tissues of the NTD models. Methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq) were performed on the NovaSeq platform and Illumina HiSeq 2,500 platform, respectively. Differentially m6A-methylated differentially expressed lncRNAs (DElncRNAs) and differentially expressed genes (DEGs) were identified, followed by GO biological process and KEGG pathway functional enrichment analyses. Expression levels of several DElncRNAs and DEGs were evaluated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR) for validation.Results: m6A levels and METTL3 expression levels were significantly lower in the brain tissues of the NTD mouse model than in controls. By integrating MeRIP-seq and RNA-seq data, 13 differentially m6A-methylated DElncRNAs and 170 differentially m6A-methylated DEGs were identified. They were significantly enriched in the Hippo signaling pathway and mannose-type O-glycan biosynthesis. The qRT-PCR results confirmed the decreased expression levels of lncRNAs, such as Mir100hg, Gm19265, Gm10544, and Malat1, and genes, such as Zfp236, Erc2, and Hmg20a, in the NTD group.Conclusion:METTL3-mediated m6A modifications may be involved in NTD development. In particular, decreased expression levels of Mir100hg, Gm19265, Gm10544, Malat1, Zfp236, Erc2, and Hmg20a may contribute to the development of NTD.

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“…The Hippo signaling pathway regulates overall organ size in several systems [ 41 ]. In the brain, it regulates the size of the cortical hem, progenitor proliferation, basal progenitor expansion, synaptic development, corpus callosum formation, and astrocyte differentiation [ 42 , 43 ]. Many of these functions overlap with those reported for Lhx2 .…”

Section: Discussionmentioning

confidence: 99%

Regulation of chromatin accessibility and gene expression in the developing hippocampal primordium by LIM-HD transcription factor LHX2

Suresh,

Muralidharan,

Pradhan

et al. 2023

PLoS Genet

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In the mammalian cerebral cortex, the hippocampal primordium (Hcp) occupies a discrete position in the dorsal telencephalic neuroepithelium adjacent to the neocortical primordium (Ncp). We examined transcriptomic and chromatin-level features that distinguish the Hcp from the Ncp in the mouse during the early neurogenic period, embryonic day (E)12.5. ATAC-seq revealed that the Hcp was more accessible than the Ncp at this stage. Motif analysis of the differentially accessible loci in these tissues revealed LHX2 as a candidate transcription factor for modulating gene regulatory networks (GRNs). We analyzed LHX2 occupancy profiles and compared these with transcriptomic data from control and Lhx2 mutant Hcp and Ncp at E12.5. Our results revealed that LHX2 directly regulates distinct genes in the Hcp and Ncp within a set of common pathways that control fundamental aspects of development namely pluripotency, axon pathfinding, Wnt, and Hippo signaling. Loss of Lhx2 caused a decrease in accessibility, specifically in hippocampal chromatin, suggesting that this factor may play a unique role in hippocampal development. We identified 14 genes that were preferentially enriched in the Hcp, for which LHX2 regulates both chromatin accessibility and mRNA expression, which have not thus far been examined in hippocampal development. Together, these results provide mechanistic insight into how LHX2 function in the Hcp may contribute to the process by which the hippocampus acquires features distinct from the neocortex.

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The Role of Hippo Signaling Pathway in the Development of the Nervous System

Cited by 13 publications

References 86 publications

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

The FSGS disease gene product and nuclear pore protein NUP205 regulates nuclear localization and activity of the transcriptional regulators YAP and TAZ in podocytes

Identifying key m6A-methylated lncRNAs and genes associated with neural tube defects via integrative MeRIP and RNA sequencing analyses

Regulation of chromatin accessibility and gene expression in the developing hippocampal primordium by LIM-HD transcription factor LHX2

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