Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content

Papes, Fábio; Camargo, Antônio Pedro; Souza, Janaína Sena de; Carvalho, Vinicius Miessler de Andrade; Szeto, Ryan A.; LaMontagne, Erin; Teixeira, José R.; Avansini, Simoni Helena; Sánchez-Sánchez, Sandra M; Nakahara, Thiago Seike; Santo, Carolina N.; Wu, Weiqiang; Yao, Heng‐Chen; Araújo, Barbara M P; Velho, Paulo Eduardo Neves Ferreira; Haddad, Gabriel G.; Muotri, Alysson R.

doi:10.1038/s41467-022-29942-w

Cited by 33 publications

(20 citation statements)

References 71 publications

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“…S8a ). In particular, some highly conserved TFs such as the regulator of neural stem cells tcf4 51 and the known neural developmental regulator lhx6 52 were detected in four species (Fig. S8a ).…”

Section: Resultsmentioning

confidence: 99%

Cell landscape of larval and adult Xenopus laevis at single-cell resolution

Yuan

Guo

et al. 2022

Nat Commun

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The rapid development of high-throughput single-cell RNA sequencing technology offers a good opportunity to dissect cell heterogeneity of animals. A large number of organism-wide single-cell atlases have been constructed for vertebrates such as Homo sapiens, Macaca fascicularis, Mus musculus and Danio rerio. However, an intermediate taxon that links mammals to vertebrates of more ancient origin is still lacking. Here, we construct the first Xenopus cell landscape to date, including larval and adult organs. Common cell lineage-specific transcription factors have been identified in vertebrates, including fish, amphibians and mammals. The comparison of larval and adult erythrocytes identifies stage-specific hemoglobin subtypes, as well as a common type of cluster containing both larval and adult hemoglobin, mainly at NF59. In addition, cell lineages originating from all three layers exhibits both antigen processing and presentation during metamorphosis, indicating a common regulatory mechanism during metamorphosis. Overall, our study provides a large-scale resource for research on Xenopus metamorphosis and adult organs.

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Section: Resultsmentioning

confidence: 99%

Cell landscape of larval and adult Xenopus laevis at single-cell resolution

Yuan

Guo

et al. 2022

Nat Commun

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“…The most consistent phenotype we report across network development, using a variety of assays (Ca 2+ imaging, MEA, sEPSC frequency), is a deficit in network-wide neuronal spiking. Importantly, these phenotypes are consistent across human and mouse PTHS models 52,53 . However, we extended these findings by identifying several cellular and molecular mechanisms underlying the reduced network activity in these PTHS models.…”

Section: Discussionmentioning

confidence: 53%

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

Davis

Chen

Ostlund

et al. 2023

Preprint

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Genetic variation in the transcription factor 4 (TCF4) gene is associated with risk for a variety of developmental and psychiatric conditions, which includes a syndromic form of ASD called Pitt Hopkins Syndrome (PTHS). TCF4 encodes an activity-dependent transcription factor that is highly expressed during cortical development and in animal models is shown to regulate various aspects of neuronal development and function. However, our understanding of how disease-causing mutations in TCF4 confer pathophysiology in a human context is lacking. Here we show that cortical neurons derived from patients with TCF4 mutations have deficits in spontaneous synaptic transmission, network excitability and homeostatic plasticity. Transcriptomic analysis indicates these phenotypes result from altered expression of genes involved in presynaptic neurotransmission and identifies the presynaptic binding protein, RIMBP2 as the most differentially expressed gene in PTHS neurons. Remarkably, TCF4-dependent deficits in spontaneous synaptic transmission and network excitability were rescued by increasing RIMBP2 expression in presynaptic neurons. Together, these results identify TCF4 as a critical transcriptional regulator of human synaptic development and plasticity and specifically identifies dysregulation of presynaptic function as an early pathophysiology in PTHS.

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“…TCF4 gene encodes a widely expressed class I basic helix-loop-helix (bHLH) transcription factor that has a critical role in the developing brain (de Pontual et al, 2009;Kim et al, 2020;Papes et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

“…Haploinsufficient TCF4 neural progenitors have decreased capacity to proliferate and differentiate into neurons (Papes et al, 2022). Pitt-Hopkins syndrome (PTHS; MIM# 610954) is a neurodevelopmental condition caused by heterozygous pathogenic variants in TCF4 gene, with most variants arising de novo (Amiel et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…TCF4 gene encodes a widely expressed class I basic helix–loop–helix (bHLH) transcription factor that has a critical role in the developing brain (de Pontual et al, 2009; Kim et al, 2020; Papes et al, 2022). Haploinsufficient TCF4 neural progenitors have decreased capacity to proliferate and differentiate into neurons (Papes et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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A typical variant in TCF4 exon 18 is not associated with Pitt–Hopkins syndrome but with a familial case of mild and nonspecific neurodevelopmental disorder

Aldeeri

Abu‐El‐Haija

2022

American J of Med Genetics Pt A

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TCF4 gene encodes a class I helix–loop–helix transcription factor critical for the developing brain. Common polymorphisms in TCF4 and disruptive variants in the proximal region of the gene have been linked to relatively mild neuropsychiatric or neurodevelopmental disorders. In contrast, variants impacting distal exons are associated with Pitt–Hopkins syndrome (PTHS), a severe autosomal dominant condition characterized by profound intellectual disability, developmental delay, limited or absent speech, distinctive facies, and disordered breathing. Although phenotypic variability has been observed in PTHS, intellectual impairment and significant speech and motor delays are invariably present. In contrast to the typical de novo variants causing TCF4‐related disorder and PTHS, we report a familial form of TCF4‐related disorder where the missense variant arose de novo in the father and was inherited by two of his children. Although this family's variant's position in exon 18 predicted a typical PTHS phenotype, none of the affected individuals met the clinical diagnostic criteria for PTHS suggested by Zollino et al. in the first international consensus statement (as in the study by Zollino et al. in 2019). Rather, the three affected family members exhibited remarkably variable and milder phenotypes than would have been predicted from the position of their TCF4 variant. Thus, the clinical spectrum of PTHS‐associated TCF4 variants may be broader than previously reported.

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Transcription Factor 4 loss-of-function is associated with deficits in progenitor proliferation and cortical neuron content

Cited by 33 publications

References 71 publications

Cell landscape of larval and adult Xenopus laevis at single-cell resolution

Cell landscape of larval and adult Xenopus laevis at single-cell resolution

TCF4 mutations disrupt synaptic function through dysregulation of RIMBP2 in patient-derived cortical neurons

A typical variant in TCF4 exon 18 is not associated with Pitt–Hopkins syndrome but with a familial case of mild and nonspecific neurodevelopmental disorder

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