Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior

Bocchi, Riccardo; Égervári, Kristóf; Carol-Perdiguer, Laura; Viale, Beatrice; Quairiaux, Charles; Roo, Mathias De; Boitard, Michael; Oskouie, Suzanne; Salmon, Patrick; Kiss, József Zoltán

doi:10.1038/s41467-017-01046-w

Cited by 68 publications

(57 citation statements)

References 71 publications

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“…DDX3X has been reported to influence canonical Wnt signaling (Cruciat et al, 2013;Snijders Blok et al, 2015), which has known roles in progenitors and migrating neurons during corticogenesis (Bocchi et al, 2017;Harrison-Uy and Pleasure, 2012). Therefore, we examined during these critical phases of brain development.…”

Section: Wnt Signaling Is Not Affected In the Developing Neocortexmentioning

confidence: 99%

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Lennox

Jiang

Suit

et al. 2018

Preprint

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De novo germline mutations in the RNA helicase DDX3X account for 1-3% of unexplained intellectual disability (ID) cases in females, and are associated with autism, brain malformations, and epilepsy. Yet, the developmental and molecular mechanisms by which DDX3X mutations impair brain function are unknown. Here we use human and mouse genetics, and cell biological and biochemical approaches to elucidate mechanisms by which pathogenic DDX3X variants disrupt brain development. We report the largest clinical cohort to date with DDX3X mutations (n=78), demonstrating a striking correlation between recurrent dominant missense mutations, polymicrogyria, and the most severe clinical outcomes. We show that Ddx3x controls cortical development by regulating neuronal generation and migration. Severe DDX3X missense mutations profoundly disrupt RNA helicase activity and induce ectopic RNA-protein granules and aberrant translation in neural progenitors and neurons. Together, our study demonstrates novel mechanisms underlying DDX3X syndrome, and highlights roles for RNA-protein aggregates in the pathogenesis of neurodevelopmental disease.

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Section: Wnt Signaling Is Not Affected In the Developing Neocortexmentioning

confidence: 99%

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

Lennox

Jiang

Suit

et al. 2018

Preprint

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“…It was shown that NAP could enhance microtubule assembly and neurite outgrowth by interacting with tubulin, and protect neurons and glia exposed to toxins in mouse and rat models 15, 16 . Recently, it was shown that the major symptoms of the Helsmoortel-Van der Aa syndrome, such as developmental delays, vocalization impairments, motor and pace dysfunctions, and social and object memory impediments, could be partially ameliorated by daily NAP administration 17, 18 . We wondered whether NAP alone could be sufficient to interact with β-Catenin.…”

Section: Resultsmentioning

confidence: 99%

“…9b-g). It is well-known that Wnt signaling plays key roles in cell fate determination, differentiation, proliferation and apoptosis 18 .…”

Section: Resultsmentioning

confidence: 99%

ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

Sun

Peng

Cao

et al. 2019

Preprint

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5 ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective 6 protein whose aberrant expression has been frequently linked to neural developmental 7 disorders, including the Helsmoortel-Van der Aa syndrome. However, its role in 8 neural development and pathology remains unclear. Using mESC (mouse embryonic 9 stem cell) directional neural differentiation as a model, we show that ADNP is 10 required for ESC neural induction and neuronal differentiation by maintaining Wnt 11 signaling. Mechanistically, ADNP functions to maintain the proper protein levels of 12 β-Catenin through binding to its armadillo domain which prevents its association with 13 key components of the degradation complex: Axin and APC. Loss of ADNP promotes 14 the formation of the degradation complex and hyperphosphorylation of β-Catenin by 15 GSK3β and subsequent degradation via ubiquitin-proteasome pathway, resulting in 16 down-regulation of key neuroectoderm developmental genes. We further show that 17 ADNP plays key role in cerebellar neuron formation. Finally, adnp gene disruption in 18 zebrafish embryos recapitulates key features of the mouse phenotype, including the 19 reduced Wnt signaling, defective embryonic cerebral neuron formation and the 20 massive neuron death. Thus, our work provides important insights into the role of 21 ADNP in neural development and the pathology of the Helsmoortel-Van der Aa 22 syndrome caused by ADNP gene mutation. 23 24 42 of mouse embryos. 43 De novo mutations in ADNP gene have recently been linked to neural 44 developmental disorders, including the Helsmoortel-Van der Aa syndrome 6 . Patients 45 display multiple symptoms, usually manifesting in early childhood with features such 46 as intellectual disability, facial dysmorphism, motor dysfunction and developmental 47 65 development which would be useful for understanding the pathology of the 66 Helsmoortel-Van der Aa syndrome caused by ADNP mutation. 67 . 68 69 70 Results 71Generation and characterization of Adnp-/-ESCs. To understand the molecular 72 function of ADNP, we generated Adnp mutant ESCs by using CRISPR/Cas9 73 technology. gRNAs were designed to target the 3' end of exon 4 of mouse Adnp gene 74 ( Fig. 1a). We have successfully generated 2 Adnp mutant alleles (-4 and -5 bp), 75 revealed by DNA genotyping around the CRISPR targeting site ( Fig. 1b). ADNP 76 protein was hardly detectable in Adnp-/-ESCs by Western blot using ADNP 77 antibodies from different resources ( Fig. 1c), which strongly indicated that the mutant 78 alleles are functional nulls. 79 In the traditional self-renewal medium containing LIF-KSR plus FBS, the newly 80 established Adnp-/-ESC colonies overall exhibited typical ESC-like morphology (Fig. 81 1d). To understand how loss of Adnp affected the global gene expression, we 82 performed RNA-sequencing (RNA-seq) experiments for control and early passaged 83Adnp-/-ESCs. Our RNA-seq analysis showed that the primitive endoderm genes such 84 as Gata6, Gata4, Sox17, Sox7 and Sparc were slightly up-regul...

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“…Wnt proteins are known to play major roles in directing neuronal migration and axondendritic guidance in vertebrates (Bocchi et al, 2017;Yoshikawa et al, 2003). In C.…”

Section: Introductionmentioning

confidence: 99%

Protein Disulfide Isomerases Control the Secretion of Wnt proteins

Torpe

Gopal

Balatci

et al. 2018

Preprint

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Strains were grown using standard growth conditions on NGM agar at 20 0 C on Escherichia coli OP50, unless otherwise stated (Brenner, 1974).Neuroanatomical reporter strains used -mgIs70 Is ;LGIV zdIs13:Is . Detailed strain information is detailed in Table S2. Molecular cloning Ppdi-1::pdi-1 cDNA rescue constructThe Ppdi-1::pdi-1 cDNA rescue construct was generated by cloning the 841 bp pdi-1 promoter with SphI-SmaI into the pPD49.26 vector and then the pdi-1 cDNA using NheI-SacI. Pdpy-7::pdi-1 cDNA rescue constructThe Pdpy-7::pdi-1 cDNA rescue construct was generated by cloning pdi-1 cDNA with NheISacI into a dpy-7 expression vector. Pdpy-7::pdi-1 cDNA -HEEL rescue constructThe Pdpy-7::pdi-1 cDNA -HEEL rescue construct was generated using site-directed mutagenesis to remove the 12 nucleotides that encode HEEL at the C-terminus of the PDI-1 protein. Pegl-20::pdi-1 cDNA rescue constructThe Pegl-20::pdi-1 cDNA rescue construct was generated by cloning the 1910 bp egl-20 promoter with SphI-SmaI into the pPD49.26 vector containing the pdi-1 cDNA. Plin-44::pdi-1 cDNA rescue constructThe Plin-44::pdi-1 cDNA rescue construct was generated by cloning the 1150 bp lin-44 promoter with SphI-SmaI into the pPD49.26 vector containing the pdi-1 cDNA.

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Perturbed Wnt signaling leads to neuronal migration delay, altered interhemispheric connections and impaired social behavior

Cited by 68 publications

References 71 publications

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

PathogenicDDX3Xmutations impair RNA metabolism and neurogenesis during fetal cortical development

ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling

Protein Disulfide Isomerases Control the Secretion of Wnt proteins

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