Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation

Zhang, Ke; Yu, Fang; Zhu, Jian; Han, Shichao; Chen, Jiehui; Wu, Xingqiang; Chen, Yingying; Shen, Tingyu; Liao, Jiaoyang; Guo, Wenxiu; Yang, Xiong-Li; Wang, Ran; Qian, Yun; Yang, Jiaxin; Cheng, Leping; Zhao, Yun; Hui, Chi‐chung; Li, Jinsong; Peng, Guangdun; He, Shuai; Jing, Naihe; Tang, Ke

doi:10.1016/j.celrep.2020.03.085

Cited by 44 publications

(42 citation statements)

References 138 publications

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“…3a). [23][24][25] Additionally, an in situ hybridization assay to detect PRKAR1B messenger RNA (mRNA) (RNAscope) revealed high PRKAR1B expression in the pituitary, diencephalon, mesencephalon, and hypothalamus in human embryos at Carnegie stage 22 (Fig. 3b).…”

Section: Resultsmentioning

confidence: 99%

“…We propose a PRKAR1B-associated NDD with GDD, ASD, neurologic anomalies, and cognitive impairment (no formal IQ scores have yet been obtained from the reported individuals) as principal features. Future research should focus on better understanding the functional consequences of PRKAR1B variants, as well [23][24][25] For each individual set of expression data (ESC, NPC, and NCC), 0% reflects the gene with the lowest, and 100% the gene with the highest level of expression. The median expression level of each data set is 50% (dashed line).…”

Section: Discussionmentioning

confidence: 99%

“…Comparison of RNA-Seq expression levels. For comparing RNA-Seq expression levels of different data sets from different sources [23][24][25] (e.g., different experimental setup and analysis software), a normalization of the provided expression scores was necessary. We derived the distribution of expression scores over all genes and calculated the percentile of each gene of interest within this distribution.…”

Section: Statisticsmentioning

confidence: 99%

“…Fig.3Expresssion of PRKAR1B during human development. (a) Normalized expression levels of different PRKAR genes and a selection of reporter genes in embryonic stem cells (ESCs), neural progenitor cells (NPCs), and neural crest cells (NCCs), based on RNA-Seq data from different sources [23][24][25]. For each individual set of expression data (ESC, NPC, and NCC), 0% reflects the gene with the lowest, and 100% the gene with the highest level of expression.…”

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confidence: 99%

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Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Marbach

Stoyanov

Erger

et al. 2021

Genetics in Medicine

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Purpose We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1β subunit of the cyclic AMP-dependent protein kinase A (PKA). Methods Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development. Results Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs. Conclusion Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Statisticsmentioning

confidence: 99%

mentioning

confidence: 99%

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Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Marbach

Stoyanov

Erger

et al. 2021

Genetics in Medicine

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“…The limitation of generating homogeneous neuronal cell populations is that we may have dismissed some developmental cellular deficits that may be relevant for ASD phenotypes. Such deficits could include proliferation of precursor cells, differential generation of various neuronal subclasses, e.g., number of excitatory vs. inhibitory neurons 52 , 53 , and alterations in astroglial cell development that is present in some ASD phenotypes and occurs in unsorted iPSC-derived neural cell populations during long-term culturing in vitro 54 . However, production of enriched DA neuron populations enabled us to detect disease phenotypes in a specific neuronal population that has a key role in the development of the 16p11.2 CNV disorders.…”

Section: Discussionmentioning

confidence: 99%

16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro

et al. 2021

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Reciprocal copy number variations (CNVs) of 16p11.2 are associated with a wide spectrum of neuropsychiatric and neurodevelopmental disorders. Here, we use human induced pluripotent stem cells (iPSCs)-derived dopaminergic (DA) neurons carrying CNVs of 16p11.2 duplication (16pdup) and 16p11.2 deletion (16pdel), engineered using CRISPR-Cas9. We show that 16pdel iPSC-derived DA neurons have increased soma size and synaptic marker expression compared to isogenic control lines, while 16pdup iPSC-derived DA neurons show deficits in neuronal differentiation and reduced synaptic marker expression. The 16pdel iPSC-derived DA neurons have impaired neurophysiological properties. The 16pdel iPSC-derived DA neuronal networks are hyperactive and have increased bursting in culture compared to controls. We also show that the expression of RHOA is increased in the 16pdel iPSC-derived DA neurons and that treatment with a specific RHOA-inhibitor, Rhosin, rescues the network activity of the 16pdel iPSC-derived DA neurons. Our data suggest that 16p11.2 deletion-associated iPSC-derived DA neuron hyperactivation can be rescued by RHOA inhibition.

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Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

et al. 2023

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Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, and mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer. Here, we review the literature and ask how the shared features can lead to different medical conditions and why having an NDD first can increase the chances of malignancy. To explore these vital questions, we focus on dysregulated PI3K/mTOR, a major brain cell growth pathway in differentiation, and MAPK, a critical pathway in proliferation, a hallmark of cancer. Differentiation is governed by chromatin organization, making aberrant chromatin remodelers highly likely agents in NDDs. Dysregulated chromatin organization and accessibility influence the lineage of specific cell brain types at specific embryonic development stages. PAK1, with pivotal roles in brain development and in cancer, also regulates MAPK. We review, clarify, and connect dysregulated pathways with dysregulated proliferation and differentiation in cancer and NDDs and highlight PAK1 role in brain development and MAPK regulation. Exactly how PAK1 activation controls brain development, and why specific chromatin remodeler components, e.g., BAF170 encoded by SMARCC2 in autism, await clarification.

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Imbalance of Excitatory/Inhibitory Neuron Differentiation in Neurodevelopmental Disorders with an NR2F1 Point Mutation

Cited by 44 publications

References 138 publications

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain

16p11.2 deletion is associated with hyperactivation of human iPSC-derived dopaminergic neuron networks and is rescued by RHOA inhibition in vitro

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

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