Spin1z induces the male pathway in the chicken by down-regulating Tcf4.

SPINDLIN1-Z (SPIN1Z), a member of the Spin/Ssty(Y-linked spermiogenesis specific transcript) protein family, participates in the early embryonic development process. Our previous RNA-seq analysis indicates that the level of Spin1z was abundantly expressed in male embryonic stem cells (ESCs) and primitive germ cells (PGCs), we speculate that Spin1z may play an important role in chicken male differentiation. Therefore, the loss- and gain-of-function experiments provide solid evidence that Spin1z is both necessary and sufficient to initiate male development in chicken. Furthermore, chromatin immunoprecipitation (ChIP) assay and the dual-luciferase assay was performed to further confirm that Spin1z contributed to chicken male differentiation by inhibiting the Tcf4 transcription. Our findings provide a novel insight into the molecular mechanism for chicken male differentiation.

Transcription Factor 4 Safeguards Hippocampal Dentate Gyrus Development by Regulating Neural Progenitor Migration.

The dentate gyrus (DG) of the hippocampal formation plays essential roles in learning and memory. Defective DG development is associated with neurological disorders. Here, we show that transcription factor 4 (Tcf4) is essential for DG development. Tcf4 expression is elevated in neural progenitors of the dentate neuroepithelium in the developing mouse brain. We demonstrate that conditional disruption of Tcf4 in the dentate neuroepithelium leads to abnormal neural progenitor migration guided by disorganized radial glial fibers, which further leads to hypoplasia in the DG. Moreover, we reveal that Wnt7b is a key downstream effector of Tcf4 in regulating neural progenitor migration. Behavioral analysis shows that disruption of integrity of the DG impairs the social memory highlighting the importance of proper development of the DG. These results reveal a critical role for Tcf4 in regulating DG development. As mutations in TCF4 cause Pitt-Hopkins syndrome (PTHS) characterized by severe intellectual disability, our data also potentially provide insights into the basis of neurological defects linked to TCF4 mutations.

Knockdown of long non-coding RNA TINCR decreases radioresistance in colorectal cancer cells.

An increasing number of studies have revealed the role of long non-coding RNAs in cancer. However, the mechanisms of action and functional utility in colorectal cancer (CRC) have not been fully elucidated. Here we describe the functional role and potential mechanism of TINCR (terminal differentiation-induced non-coding RNA) in CRC. Firstly, TINCR was selected using sequencing analyses and the starBase database. Cell Counting Kit-8, scratch wound healing, and transwell assays revealed that TINCR inhibited proliferation and migration in SW620 and HTC116 cells. Intriguingly, TINCR expression was up-regulated in a radioresistant CRC cell line (SW620R). Although TINCR had no significant effects on SW620R cell proliferation or migration, knockdown of TINCR reduced the radioresistance, and its overexpression had opposite effects. We then focused on transcription factor 4 (TCF4) as it is downregulated in CRC and associated with increased stemness in tumors. We found that TINCR and TCF4 levels were positively related in SW620R cells. TINCR knockdown reduced sphere formation ability in SW620R cells. TINCR also suppressed the OCT4 and SOX2 stemness genes, despite having no effect on NANOG. The expression levels of these genes were substantially higher in SW620R than in SW620 cells. To further explore the mechanism of TINCR and radioresistance, miR-137 was analyzed as it targets TCF4. We firstly confirmed that TCF4 is a target of miR-137. We then identified that TINCR knockdown enhanced miR-137 expression in SW620R cells. Collectively, these findings suggest that TINCR knockdown inhibits TCF4 by regulating miR-137 expression.

Self-Renewal and Toll-like Receptor Signaling Sustain Exhausted Plasmacytoid Dendritic Cells during Chronic Viral Infection.

Although characterization of T cell exhaustion has unlocked powerful immunotherapies, the mechanisms sustaining adaptations of short-lived innate cells to chronic inflammatory settings remain unknown. During murine chronic viral infection, we found that concerted events in bone marrow and spleen mediated by type I interferon (IFN-I) and Toll-like receptor 7 (TLR7) maintained a pool of functionally exhausted plasmacytoid dendritic cells (pDCs). In the bone marrow, IFN-I compromised the number and the developmental capacity of pDC progenitors, which generated dysfunctional pDCs. Concurrently, exhausted pDCs in the periphery were maintained by self-renewal via IFN-I- and TLR7-induced proliferation of CD4- subsets. On the other hand, pDC functional loss was mediated by TLR7, leading to compromised IFN-I production and resistance to secondary infection. These findings unveil the mechanisms sustaining a self-perpetuating pool of functionally exhausted pDCs and provide a framework for deciphering long-term exhaustion of other short-lived innate cells during chronic inflammation.

The importance of TCF4 gene in the etiology of recurrent depressive disorders.

BACKGROUND: A recurrent depressive disorder is one of the most commonly diagnosed disease entities among psychiatric disorders. The prevalence and morbidity of depression are constantly increasing. Numerous studies have demonstrated the role of genetic factors in the etiology of depressive disorders. Many studies are being conducted to identify genes that predispose to depression. The purpose of this study was to investigate the role of TCF4 gene in the etiology of recurrent depressive disorders and, in particular, to assess expression of the TCF4 gene at the mRNA and protein level in patients with recurrent depressive disorders versus healthy individuals. MATERIAL AND METHODS: The examined population consisted of 170 individuals suffering from depression and 90 healthy individuals. The expressions of the TCF4 gene at the mRNA and protein level were assessed. RESULTS: Decreased TCF4 expression at the mRNA and protein level was found in patients with depressive disorder versus healthy individuals. Expression of the studied gene was not affected by the patients' sex and age. The statistical analysis also showed no correlation between the expression of TCF4 at the mRNA and protein level and the number of episodes or the severity of symptoms. Among the clinical manifestations of depression, only the duration of the illness correlated with the expression of TCF4 at the mRNA level. CONCLUSIONS: Expression of TCF4 at the mRNA and protein level may be significant in the pathomechanism of recurrent depressive disorder and it is not dependent on sex and age.

CTG18.1 repeat expansion may reduce TCF4 gene expression in corneal endothelial cells of German patients with Fuchs' dystrophy.

PURPOSE: It was the aim of this investigation to elucidate the functional effects of CTG18.1 trinucleotide repeat expansion and the polymorphism rs613872 in the transcription factor 4 (TCF4) in corneas of patients affected by Fuchs' endothelial corneal dystrophy (FECD). METHODS: Sixty-one unrelated German patients with FECD and 113 unaffected controls were investigated and genotyped for the CTG18.1 locus by triplet primed PCR (TP-PCR) and the rs613872 polymorphism via Sanger sequencing and by employing genomic DNA from peripheral blood leucocytes. DNA and RNA retrieved from human corneal endothelial explants were examined for alterations in the gene expression of TCF4, ZEB1, E-cadherin, N-cadherin, as well as the CTG18.1 locus. RESULTS: The CTG18.1 trinucleotide repeat expansion (>50 repeats) was detected in the peripheral blood in 77% of affected FECD patients and 11.5% of the healthy volunteers. Applying the TP-PCR method, the length of CTG18.1 repeat expansions correlates in the blood and corneal cells. We noted that the CTG18.1 trinucleotide repeat expansion was associated with reduced TCF4 and ZEB1 gene expression, especially in the explanted corneal endothelial cells. While E-cadherin gene expression was not detected in any corneal endothelial cells, expression of CDH2 (N-cadherin) was detected in FECD-affected endothelium and in our controls. CONCLUSIONS: The CTG18.1 repeat expansion may reduce gene expression of TCF4 and ZEB1, suggesting that a mechanism triggering a loss of function may contribute to FECD. The correlation of CTG18.1 repeat expansion from blood and the cornea may represent the first step toward investigating the potential relevance of testing the blood of cornea donors to minimize the risk of transplanting grafts potentially affected with FECD.