Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

Bem, Joanna; Brożko, Nikola; Chakraborty, Chaitali; Lipiec, Marcin Andrzej; Koziński, Kamil; Nagalski, Andrzej; Szewczyk, Łukasz Mateusz; Wisniewska, M.

doi:10.1002/1873-3468.13502

Cited by 65 publications

(57 citation statements)

References 150 publications

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“…In fact, the strongest locus identified in our secondary GxS interaction analyses for SCZ (using the PGC dataset) (rs13270586; p=1.55×10 −7 ) was near C8orf4 (aka TCIM), which functions as a positive regulator of the Wnt/ß-catenin signaling pathway that has a central role in fundamental neuronal processes-including synaptogenesis, axon guidance, and dendrite development (59)-and a pathway previously implicated in SCZ, BIP, and MDD (60)(61)(62)(63).…”

Section: Discussionmentioning

confidence: 92%

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Blokland¹,

Grove²,

Chen³

et al. 2020

Preprint

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BACKGROUND: Sex differences in the incidence and/or presentation of schizophrenia (SCZ), major depressive disorder (MDD), and bipolar disorder (BIP) are pervasive. Previous evidence for shared genetic risk and sex differences in brain abnormalities across these disorders suggest possible shared sex-dependent genetic risk. METHODS: We conducted the largest to date genome-wide genotype-by-sex (GxS) interaction analysis of risk for these disorders, using data from 85,735 cases (33,403 SCZ, 19,924 BIP, 32,408 MDD) and 109,946 controls from the Psychiatric Genomics Consortium (PGC) and iPSYCH. RESULTS: Across disorders, genome-wide significant SNP-by-sex interaction was detected for a locus encompassing NKAIN2 gene (rs117780815; p=3.2x10-8), that interacts with sodium/potassium-transporting ATPase enzymes important for neuronal excitability. Three additional loci showed evidence (p<1x10-6) for cross-disorder GxS interaction (rs7302529, p=1.6x10-7; rs73033497, p=8.8x10-7; rs7914279, p=6.4x10-7) with various potential functions. Gene-based analyses identified GxS interaction across disorders (p=8.97x10-7) with transcriptional inhibitor SLTM. Most significant in SCZ was a locus in the MOCOS gene (rs11665282; p=1.5x10-7), implicating vascular endothelial cells. Secondary analysis of the SCZ PGC dataset detected a noteworthy interaction (rs13265509; p=1.1x10-7) in a locus containing IDO2, a kynurenine pathway enzyme with an immunoregulatory function previously implicated in SCZ, BIP, and MDD. Pathway enrichment analysis detected significant GxS of genes regulating vascular endothelial growth factor (VEGF) receptor signaling in MDD (pFDR<0.05). CONCLUSIONS: In the largest genome-wide GxS analysis of mood and psychotic disorders to date, there was substantial genetic overlap between the sexes. However, significant sex-dependent effects were enriched for genes related to neuronal development, immune and vascular functions across and within SCZ, BIP, and MDD at the variant, gene, and pathway enrichment levels.

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Section: Discussionmentioning

confidence: 92%

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Blokland¹,

Grove²,

Chen³

et al. 2020

Preprint

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“…Involvement of TCF7L2 as the putative effector of the altered signalling in neurons is particularly intriguing since TCF7L2 locus has been genetically associated with mental disorders like scizophrenia in humans (Bem et al, 2019). Moreover, transgenic mice have revealed a dose-dependent role for Tcf7l2 in fear-conditioning and anxiety, traits for which Gui et al: Single nuclei ATAC-seq of midbrain cell types 2 2 A/J is known to significantly differ from C57BL/6J (Ponder et al, 2007;Portugal et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

“…Understanding how Wnt signalling activity is altered between the mouse strains requires further analysis. However, it is interesting to note that expression of Wnt2b, upstream ligand of Wnt pathway genetically associated with bipolar disorder (Bem et al, 2019), is significantly decreased in the ventral midbrain of A/J compared to C57BL/6J (Gui et al, 2020). Thus, providing one possible explanation.…”

Section: Discussionmentioning

confidence: 99%

Single nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell type-specific gene regulatory variation

Gui

Grzyb

Thomas

et al. 2020

Preprint

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Gui et al.: Single nuclei ATAC-seq of midbrain cell types 2 SUMMARY Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility such as Parkinson's disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression. We report 20 658 single nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains.We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell type-specific key transcription factors.Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Our dataset provides an extensive resource to study gene regulation in mesencephalon.

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“…Tcf7l2, a risk gene for schizophrenia and autism (Bem et al, 2019) that encodes a member of the LEF1/TCF transcription factor family (Cadigan and Waterman, 2012), is the only shared marker of prosomere 2 neurons (Nagalski et al, 2013;Nagalski et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

Lipiec

Koziński

Zajkowski

et al. 2019

Preprint

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StatementThe study describes a role of TCF7L2 in neuronal differentiation of thalamic glutamatergic neurons at two developmental stages, highlighting its involvement in the postnatal establishment of critical thalamic electrophysiological features. AbstractNeuronal phenotypes are controlled by terminal selector transcription factors in invertebrates, but few examples of such regulators have been provided in vertebrates. TCF7L2 has been identified as a regulator of efferent outgrowth in the thalamus and habenula. We used a complete and conditional knockout of Tcf7l2 in mice to investigate the hypothesis that TCF7L2 plays a dual role in thalamic neuron differentiation and functions as a terminal selector. Connectivity and cell clustering was disrupted in the thalamo-habenular region in Tcf7l2 -/embryos. The expression of subregional thalamic and habenular transcription factors was lost and region-specific cell migration and axon guidance genes were downregulated. In mice with postnatal Tcf7l2 knockout, the induction of genes that confer terminal electrophysiological features of thalamic neurons was impaired. Many of these genes proved to be TCF7L2 direct targets. The role of TCF7L2 in thalamic terminal selection was functionally confirmed by impaired firing modes in thalamic neurons in the mutant mice.These data corroborate the existence of master regulators in the vertebrate brain that maintain regional transcriptional network, control stage-specific genetic programs and induce terminal selection.of the mice colony, and Kacper Posyniak for assistance with sample staining and acquisition.

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Wnt/β‐catenin signaling in brain development and mental disorders: keeping TCF7L2 in mind

Cited by 65 publications

References 150 publications

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Sex-Dependent Shared and Non-Shared Genetic Architecture Across Mood and Psychotic Disorders

Single nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell type-specific gene regulatory variation

TCF7L2 regulates postmitotic differentiation programs and excitability patterns in the thalamus

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