Opposite Roles of Wnt7a and Sfrp1 in Modulating Proper Development of Neural Progenitors in the Mouse Cerebral Cortex

Miao, Nan; Bian, Shan; Lee, Trevor; Mubarak, Taufif; Huang, Sheng-Lung; Wen, Zhi‐Hong; Hussain, Ghulam; Sun, Tao

doi:10.3389/fnmol.2018.00247

Cited by 13 publications

(10 citation statements)

References 88 publications

(111 reference statements)

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“…For instance, Wnt7a and Wnt8a have been shown to regulate excitatory synaptic formation and the LRP6 co-receptor is critical for the development of functional synapses in vivo ( Ciani et al, 2011 ; Sharma et al, 2013 ). Moreover, a Wnt7a KO mouse shows reduced number of cortical progenitors due to increase differentiation of cells ultimately leading to microcephaly ( Miao et al, 2018 ), and similarly, during cortical development the LRP6 KO mice display a smaller and thinner cortical plate with layer VI and layers II–IV showing a marked decreased in the number of neurons ( Zhou et al, 2006 ), adding support that the Wnt/β-catenin complex receptor at the membrane has an essential role in cortical growth and lamination ( Figure 2 ). Interestingly, mutations in proteins that promote the secretion of Wnt ligands such as PORCN ( Castilla-Vallmanya et al, 2021 ) and Wntless ( Chai et al, 2021 ) have also been recently described to regulate cortical development.…”

Section: Wnt/β-catenin Signaling In Brain Development and Synaptic Function In Autism Spectrum Disordersmentioning

confidence: 99%

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Caracci

Ávila

Espinoza-Cavieres

et al. 2021

Front. Mol. Neurosci.

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Autism spectrum disorders (ASD) is a heterogeneous group of neurodevelopmental disorders characterized by synaptic dysfunction and defects in dendritic spine morphology. In the past decade, an extensive list of genes associated with ASD has been identified by genome-wide sequencing initiatives. Several of these genes functionally converge in the regulation of the Wnt/β-catenin signaling pathway, a conserved cascade essential for stem cell pluripotency and cell fate decisions during development. Here, we review current information regarding the transcriptional program of Wnt/β-catenin signaling in ASD. First, we discuss that Wnt/β-catenin gain and loss of function studies recapitulate brain developmental abnormalities associated with ASD. Second, transcriptomic approaches using patient-derived induced pluripotent stem cells (iPSC) cells, featuring mutations in high confidence ASD genes, reveal a significant dysregulation in the expression of Wnt signaling components. Finally, we focus on the activity of chromatin-remodeling proteins and transcription factors considered high confidence ASD genes, including CHD8, ARID1B, ADNP, and TBR1, that regulate Wnt/β-catenin-dependent transcriptional activity in multiple cell types, including pyramidal neurons, interneurons and oligodendrocytes, cells which are becoming increasingly relevant in the study of ASD. We conclude that the level of Wnt/β-catenin signaling activation could explain the high phenotypical heterogeneity of ASD and be instrumental in the development of new diagnostics tools and therapies.

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Section: Wnt/β-catenin Signaling In Brain Development and Synaptic Function In Autism Spectrum Disordersmentioning

confidence: 99%

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Caracci

Ávila

Espinoza-Cavieres

et al. 2021

Front. Mol. Neurosci.

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“…Western blotting also showed the decreased levels of SFRP1 as well as increase of β-catenin and Wnt7b in the isolated APOE -/- astrocytes compared to the controls ( Figure 3c-f ). Since SFRP1 is secreted by glia cells and has been shown to regulate neural differentiation by modulating Wnt signaling (38, 39), these results suggest that APOE deficiency may also impact cellular composition in the iPSC-derived cerebral organoids through Wnt/β-catenin signaling pathway by suppressing astrocytic SFRP1 production.…”

Section: Resultsmentioning

confidence: 95%

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

Zhao

Ikezu

Lü

et al. 2022

Preprint

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The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD); however, how it modulates brain homeostasis is not clear. The apoE protein is a major lipid carrier in the brain transporting lipids such as cholesterol among different brain cell types. Here, we show that APOE deficiency in human iPSC-derived cerebral organoids impacts brain lipid homeostasis by modulating multiple cellular and molecular pathways. Molecular profiling through single cell RNA-sequencing revealed that APOE deficiency leads to changes in cellular composition of isogenic cerebral organoids likely by modulating the EIF2 signaling pathway as these events were alleviated by the treatment of a pathway inhibitor ISRIB. APOE deletion also leads to activation of the Wnt/β-catenin signaling pathway with concomitant decrease of SFRP1 expression in glia cells. Importantly, the critical role of apoE in cell type-specific lipid homeostasis was observed upon APOE deletion in cerebral organoids with a specific upregulation of cholesterol biosynthesis in excitatory neurons and excessive lipid accumulation in astrocytes. Relevant to human AD, APOE4 cerebral organoids show altered neurogenesis and cholesterol metabolism compared to those with APOE3. Our work demonstrates critical roles of apoE in brain homeostasis and offers critical insights into the APOE4-related pathogenic mechanisms.

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“…Although NSCs of the SLC39A8-p.393T knock-in mice did not exhibit abnormalities in proliferation and migration, whether cortical development was affected remains unclear. We thus investigated the effect of SLC39A8-p.393T knock-in on cortical development by using four cortical layer-specific markers (TBR1, CTIP2, SOX2, SATB2) [ 31 , 32 ]. We found that the ratios of TBR1 + /DAPI + , CTIP2 + /DAPI + , SOX2 + /DAPI + , and SATB2 + /DAPI + did not show significant differences between knock-in mice and wild-types (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Coronal sections from the same cortical regions of wild-type and knock-in mice were selected to perform immunohistochemical staining. Four cortical layer-specific markers (TBR1, CTIP2, SOX2, SATB2) were used as previous paper to label the primary somatosensory cortex [ 31 , 32 ]. The primary antibodies used were rabbit anti-TBR1 (Cat.…”

Section: Methodsmentioning

confidence: 99%

The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density

et al. 2022

Transl Psychiatry

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The missense variant rs13107325 (C/T, p.Ala391Thr) in SLC39A8 consistently showed robust association with schizophrenia in recent genome-wide association studies (GWASs), suggesting the potential pathogenicity of this non-synonymous risk variant. Nevertheless, how this missense variant confers schizophrenia risk remains unknown. Here we constructed a knock-in mouse model (by introducing a threonine at the 393th amino acid of mouse SLC39A8 (SLC39A8-p.393T), which corresponds to rs13107325 (p.Ala391Thr) of human SLC39A8) to explore the potential roles and biological effects of this missense variant in schizophrenia pathogenesis. We assessed multiple phenotypes and traits (associated with rs13107325) of the knock-in mice, including body and brain weight, concentrations of metal ions (including cadmium, zinc, manganese, and iron) transported by SLC39A8, blood lipids, proliferation and migration of neural stem cells (NSCs), cortical development, behaviors and cognition, transcriptome, dendritic spine density, and synaptic transmission. Many of the tested phenotypes did not show differences in SLC39A8-p.393T knock-in and wild-type mice. However, we found that zinc concentration in brain and blood of SLC39A8-p.393T knock-in mice was dysregulated compared with wild-types, validating the functionality of rs13107325. Further analysis indicated that cortical dendritic spine density of the SLC39A8-p.393T knock-in mice was significantly decreased compared with wild-types, indicating the important role of SLC39A8-p.393T in dendritic spine morphogenesis. These results indicated that SLC39A8-p.393T knock-in resulted in decreased dendritic spine density, thus mimicking the dendritic spine pathology observed in schizophrenia. Our study indicates that rs13107325 might confer schizophrenia risk by regulating zinc concentration and dendritic spine density, a featured characteristic that was frequently reported to be decreased in schizophrenia.

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Opposite Roles of Wnt7a and Sfrp1 in Modulating Proper Development of Neural Progenitors in the Mouse Cerebral Cortex

Cited by 13 publications

References 88 publications

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

Wnt/β-Catenin-Dependent Transcription in Autism Spectrum Disorders

APOE deficiency impacts neural differentiation and cholesterol biosynthesis in human iPSC-derived cerebral organoids

The schizophrenia-associated missense variant rs13107325 regulates dendritic spine density

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