FOXG1 dose tunes cell proliferation dynamics in human forebrain progenitor cells

Hettige, Nuwan C.; Peng, Hong; Wu, Hongyan; Zhang, Xin; Yerko, Volodymyr; Zhang, Ying; Jefri, Malvin; Soubannier, Vincent; Maussion, Gilles; Alsuwaidi, Shaima; Ni, Anjie; Rocha, Cecilia; Krishnan, Jeyashree; McCarty, Vincent; Antonyan, Lilit; Schuppert, Andreas; Turecki, Gustavo; Fon, Edward A.; Durcan, Thomas M.; Ernst, Carl

doi:10.1016/j.stemcr.2022.01.010

Cited by 6 publications

(4 citation statements)

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“…DYRK1A further regulates PAX6 111 , which in turn maintains the balance between proliferation and neural specification 112,113 . Notably, mRNA expression of PAX6 (all, p < 0.0001) as well as FOXG1 (sgDYRK1A, sgDCAF7, p < 0.0001; sgKIAA0232 p = 0.0012) and SOX2 (sgDYRK1A, p = 0.0012; sgDCAF7, p = 0.0003; sgKIAA0232, p = 0.0009), markers which are expressed in NPCs and whose deficits lead to proliferation defects and changes in neuronal differentiation patterns 114,115 , were significantly reduced in all three KD NPCs ( Figure 5I ).…”

Section: Resultsmentioning

confidence: 99%

“…DYRK1A further regulates PAX6 113 , which in turn maintains the balance between proliferation and neural specification 114,115 . Notably, mRNA expression of PAX6 as well as FOXG1 and SOX2 , markers which are expressed in NPCs and whose deficits lead to proliferation defects and changes in neuronal differentiation patterns 116,117 , were significantly reduced in all three KD NPCs ( Figure 5I, Table S5; One Way ANOVA with Dunnett correction: PAX6 , all, p.adj <0.0001; FOXG1 , sgDYRK1A, sgDCAF7, p.adj < 0.0001, sgKIAA0232 p.adj = 0.0012; SOX2 sgDYRK1A, p.adj = 0.0012; sgDCAF7, p.adj = 0.0003; sgKIAA0232, p.adj = 0.0009).…”

Section: Resultsmentioning

confidence: 99%

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A foundational atlas of autism protein interactions reveals molecular convergence

Wang,

Vartak,

Zaltsman

et al. 2023

Preprint

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SummaryTranslating high-confidence (hc) autism spectrum disorder (ASD) genes into viable treatment targets remains elusive. We constructed a foundational protein-protein interaction (PPI) network in HEK293T cells involving 100 hcASD risk genes, revealing over 1,800 PPIs (87% novel). Interactors, expressed in the human brain and enriched for ASD but not schizophrenia genetic risk, converged on protein complexes involved in neurogenesis, tubulin biology, transcriptional regulation, and chromatin modification. A PPI map of 54 patient-derived missense variants identified differential physical interactions, and we leveraged AlphaFold-Multimer predictions to prioritize direct PPIs and specific variants for interrogation inXenopus tropicalisand human forebrain organoids. A mutation in the transcription factor FOXP1 led to reconfiguration of DNA binding sites and altered development of deep cortical layer neurons in forebrain organoids. This work offers new insights into molecular mechanisms underlying ASD and describes a powerful platform to develop and test therapeutic strategies for many genetically-defined conditions.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A foundational atlas of autism protein interactions reveals molecular convergence

Wang,

Vartak,

Zaltsman

et al. 2023

Preprint

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“…Prior work has shown increased S-Phase length of apical and basal progenitors in the mouse cortex with sustained Pax6 expression ( Wong et al 2015 ). Foxg1 is a regulator of neurogenic commitment ( Hanashima et al 2002 ; Hettige et al 2022 ; Wang et al 2022b ) and is upregulated in neural progenitors at E13.5 in Foxp1 cKOs (Supplemental Tables 1, 2). Yy1 , a gene involved in progenitor maintenance ( Knauss et al 2018 ), is also upregulated in DEGs / open DARs in aRGs of cKOs (Supplemental Tables 1, 2).…”

Section: Resultsmentioning

confidence: 99%

Cell type specific roles of FOXP1 during early neocortical murine development

Ortiz,

Ayhan,

Harper

et al. 2024

Preprint

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Cortical development is a tightly controlled process and any deviation during development may increase the susceptibility to neurodevelopmental disorders, such as autism spectrum disorders (ASD). Numerous studies identified mutations inFOXP1, a transcription factor enriched in the neocortex, as causal for ASD and FOXP1 syndrome. Our group has shown thatFoxp1deletion in the mouse cortex leads to overall reduced cortex thickness, alterations in cortical lamination, and changes in the relative thickness of cortical layers. However, the developmental and cell type-specific mechanisms underlying these changes remained unclear. This work characterizes the developmental requirement of neocorticalFoxp1at key embryonic and perinatal ages using a conditional knock-out ofFoxp1. We find thatFoxp1deletion results in accelerated pseudo-age during early neurogenesis, increased cell cycle exit during late neurogenesis, altered gene expression and chromatin accessibility, and selective migration deficits in a subset of upper-layer neurons. These data explain the postnatal differences observed in cortical layers and relative cortical thickness. We also highlight genes regulated by FOXP1 and their enrichment with high-confidence ASD or synaptic genes. Together, these results underscore a network of neurodevelopmental disorder-related genes that may serve as potential modulatory targets for postnatal modification relevant to ASD and FOXP1 syndrome.

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“…The FOXG1 gene, belonging to the forkhead family, plays a crucial role as a transcription factor in controlling the growth and specialization of cells (Hettige et al 2022 ). Mutations in FOXG1 gene have a negative impact on the development and differentiation of axons and neurons, including microcephaly, seizures, and profound intellectual disability.…”

Section: Discussionmentioning

confidence: 99%

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

Yun,

Ma,

Zhang

et al. 2024

Cell Mol Neurobiol

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An increasing body of research suggests that promoting microglial autophagy hinders the neuroinflammation initiated though the NLRP3 inflammasome activation in Alzheimer’s disease (AD). The function of FoxG1, a crucial transcription factor involved in cell survival by regulating mitochondrial function, remains unknown during the AD process and neuroinflammation occurs. In the present study, we firstly found that Aβ peptides induced AD-like neuroinflammation upregulation and downregulated the level of autophagy. Following low-dose Aβ25–35 stimulation, FoxG1 expression and autophagy exhibited a gradual increase. Nevertheless, with high-concentration Aβ25–35 treatment, progressive decrease in FoxG1 expression and autophagy levels as the concentration of Aβ25–35 escalated. In addition, FoxG1 has a positive effect on cell viability and autophagy in the nervous system. In parallel with the Aβ25–35 stimulation, we employed siRNA to decrease the expression of FoxG1 in N2A cells. A substantial reduction in autophagy level (Beclin1, LC3II, SQSTM1/P62) and a notable growth in inflammatory response (NLRP3, TNF-α, and IL-6) were observed. In addition, we found FoxG1 overexpression owned the effect on the activation of AMPK/mTOR autophagy pathway and siRNA-FoxG1 successfully abolished this effect. Lastly, FoxG1 suppressed the NLRP3 inflammasome and enhanced the cognitive function in AD-like mouse model induced by Aβ25–35. Confirmed by cellular and animal experiments, FoxG1 suppressed NLRP3-mediated neuroinflammation, which was strongly linked to autophagy regulated by AMPK/mTOR. Taken together, FoxG1 may be a critical node in the pathologic progression of AD and has the potential to serve as therapeutic target.

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FOXG1 dose tunes cell proliferation dynamics in human forebrain progenitor cells

Cited by 6 publications

References 50 publications

A foundational atlas of autism protein interactions reveals molecular convergence

A foundational atlas of autism protein interactions reveals molecular convergence

Cell type specific roles of FOXP1 during early neocortical murine development

FoxG1 as a Potential Therapeutic Target for Alzheimer’s Disease: Modulating NLRP3 Inflammasome via AMPK/mTOR Autophagy Pathway

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