The canonical Wnt/β-catenin signaling pathway is a central regulator of development and tissue homeostasis. In the intestine, Wnt signaling is primarily known as the principal organizer of epithelial ...stem cell identity and proliferation. Within the last decade, numerous scientific breakthroughs have shed light on epithelial self-organization in the gut, and organoids are now routinely used to study stem cell biology and intestinal pathophysiology. The contribution of non-epithelial cells to Wnt signaling in the gut has received less attention. However, there is mounting evidence that stromal cells are a rich source of Wnt pathway activators and inhibitors, which can dynamically shape Wnt signaling to control epithelial proliferation and restitution. Elucidating the extent and mechanisms of paracrine Wnt signaling in the intestine has the potential to broaden our understanding of epithelial homeostasis, and may be of particular relevance for disorders such as inflammatory bowel diseases and colitis-associated cancers.
Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in ...the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.
Functional near infrared spectroscopy (fNIRS) is a versatile neuroimaging tool with an increasing acceptance in the neuroimaging community. While often lauded for its portability, most of the fNIRS ...setups employed in neuroscientific research still impose usage in a laboratory environment. We present a wearable, multi-channel fNIRS imaging system for functional brain imaging in unrestrained settings. The system operates without optical fiber bundles, using eight dual wavelength light emitting diodes and eight electro-optical sensors, which can be placed freely on the subject's head for direct illumination and detection. Its performance is tested on N=8 subjects in a motor execution paradigm performed under three different exercising conditions: (i) during outdoor bicycle riding, (ii) while pedaling on a stationary training bicycle, and (iii) sitting still on the training bicycle. Following left hand gripping, we observe a significant decrease in the deoxyhemoglobin concentration over the contralateral motor cortex in all three conditions. A significant task-related ΔHbO2 increase was seen for the non-pedaling condition. Although the gross movements involved in pedaling and steering a bike induced more motion artifacts than carrying out the same task while sitting still, we found no significant differences in the shape or amplitude of the HbR time courses for outdoor or indoor cycling and sitting still. We demonstrate the general feasibility of using wearable multi-channel NIRS during strenuous exercise in natural, unrestrained settings and discuss the origins and effects of data artifacts. We provide quantitative guidelines for taking condition-dependent signal quality into account to allow the comparison of data across various levels of physical exercise. To the best of our knowledge, this is the first demonstration of functional NIRS brain imaging during an outdoor activity in a real life situation in humans.
•A wearable, multi-channel fNIRS imaging system is presented and tested in 8 subjects.•This is the first demonstration of fNIRS brain imaging during an outdoor activity.•The device is well feasible for functional brain imaging in real life situations.
Forkhead box (FOX) family transcription factors play essential roles in development, tissue homeostasis, and disease. Although the biology of several FOX proteins has been studied in depth, it is ...unclear to what extent these findings apply to even closely related family members, which frequently exert overlapping but non-redundant functions. To help address this question, we have generated a uniform, ready-to-use expression library of all 44 human FOX transcription factors with a convenient peptide tag for parallel screening assays. In addition, we have generated multiple universal forkhead box reporter plasmids, which can be used to monitor the transcriptional activity of most FOX proteins with high fidelity. As a proof-of-principle, we use our plasmid library to identify the DNA repair protein XRCC6/Ku70 as a selective FOX interaction partner and regulator of FOX transcriptional activity. We believe that these tools, which we make available via the Addgene plasmid repository, will considerably expedite the investigation of FOX protein biology.
The canonical Wnt signaling pathway is of paramount importance in development and disease. An emergent question is whether the upstream cascade of the canonical Wnt pathway has physiologically ...relevant roles beyond β-catenin-mediated transcription, which is difficult to study due to the pervasive role of this protein. Here, we show that transcriptionally silent spermatozoa respond to Wnt signals released from the epididymis and that mice mutant for the Wnt regulator Cyclin Y-like 1 are male sterile due to immotile and malformed spermatozoa. Post-transcriptional Wnt signaling impacts spermatozoa through GSK3 by (1) reducing global protein poly-ubiquitination to maintain protein homeostasis; (2) inhibiting septin 4 phosphorylation to establish a membrane diffusion barrier in the sperm tail; and (3) inhibiting protein phosphatase 1 to initiate sperm motility. The results indicate that Wnt signaling orchestrates a rich post-transcriptional sperm maturation program and invite revisiting transcription-independent Wnt signaling in somatic cells as well.
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•Mammalian spermatozoa are Wnt-responsive cells•Wnt signaling controls sperm maturation independent of β-catenin•Wnt ligands promote sperm proteome stability (Wnt/STOP) and sperm motility•GSK3 is a septin 4 kinase that inhibits septin clustering
Although the impact of canonical Wnt signaling is predominantly thought to necessitate β-catenin-dependent transcription, a multifaceted set of Wnt functions in sperm development is implemented post-transcriptionally through mechanisms that maybe relevant to other tissues as well.
Epithelial cells form protective barriers that physically separate an organism from the outside world. Rather than being merely static, impregnable shields, epithelia are highly dynamic structures ...that can adjust their proliferation, differentiation, and death in response to intrinsic and extrinsic signals. The advantages as well as pitfalls of this flexibility are highlighted in inflammatory disorders such as inflammatory bowel diseases and psoriasis, which are characterized by a chronically dysregulated homeostasis of the epithelium. In recent years, it has become increasingly apparent that epithelial cells communicate with their surroundings through converging, integrated signaling cascades and that even minor alterations in these pathways can have dramatic pathologic consequences. In this review, we discuss how inflammatory cytokines and other signaling molecules, directly or through cross talk, regulate epithelial homeostasis in the intestine, and we highlight parallels and differences in a few other organs.
Since the discovery of the close association between rapid eye movement (REM) sleep and dreaming, much effort has been devoted to link physiological signatures of REM sleep to the contents of ...associated dreams 1–4. Due to the impossibility of experimentally controlling spontaneous dream activity, however, a direct demonstration of dream contents by neuroimaging methods is lacking. By combining brain imaging with polysomnography and exploiting the state of “lucid dreaming,” we show here that a predefined motor task performed during dreaming elicits neuronal activation in the sensorimotor cortex. In lucid dreams, the subject is aware of the dreaming state and capable of performing predefined actions while all standard polysomnographic criteria of REM sleep are fulfilled 5, 6. Using eye signals as temporal markers, neural activity measured by functional magnetic resonance imaging (fMRI) and near-infrared spectroscopy (NIRS) was related to dreamed hand movements during lucid REM sleep. Though preliminary, we provide first evidence that specific contents of REM-associated dreaming can be visualized by neuroimaging.
► Eye signals can be used to access dream content with concurrent EEG and neuroimaging ► Dreamed hand movements correspond to activity in the contralateral sensorimotor cortex
The Wnt signaling pathway is of paramount importance for development and disease. However, the tissue-specific regulation of Wnt pathway activity remains incompletely understood. Here we identify ...FOXB2, an uncharacterized forkhead box family transcription factor, as a potent activator of Wnt signaling in normal and cancer cells. Mechanistically, FOXB2 induces multiple Wnt ligands, including WNT7B, which increases TCF/LEF-dependent transcription without activating Wnt coreceptor LRP6 or β-catenin. Proximity ligation and functional complementation assays identified several transcription regulators, including YY1, JUN, and DDX5, as cofactors required for FOXB2-dependent pathway activation. Although FOXB2 expression is limited in adults, it is induced in select cancers, particularly advanced prostate cancer. RNA-seq data analysis suggests that FOXB2/WNT7B expression in prostate cancer is associated with a transcriptional program that favors neuronal differentiation and decreases recurrence-free survival. Consistently, FOXB2 controls Wnt signaling and neuroendocrine differentiation of prostate cancer cell lines. Our results suggest that FOXB2 is a tissue-specific Wnt activator that promotes the malignant transformation of prostate cancer.
Functional neuroimaging has provided evidence for altered function of mesolimbic circuits implicated in reward processing, first and foremost the ventral striatum, in patients with schizophrenia. ...While such findings based on significant group differences in brain activations can provide important insights into the pathomechanisms of mental disorders, the use of neuroimaging results from standard univariate statistical analysis for individual diagnosis has proven difficult. In this proof of concept study, we tested whether the predictive accuracy for the diagnostic classification of schizophrenia patients vs. healthy controls could be improved using multivariate pattern analysis (MVPA) of regional functional magnetic resonance imaging (fMRI) activation patterns for the anticipation of monetary reward. With a searchlight MVPA approach using support vector machine classification, we found that the diagnostic category could be predicted from local activation patterns in frontal, temporal, occipital and midbrain regions, with a maximal cluster peak classification accuracy of 93% for the right pallidum. Region-of-interest based MVPA for the ventral striatum achieved a maximal cluster peak accuracy of 88%, whereas the classification accuracy on the basis of standard univariate analysis reached only 75%. Moreover, using support vector regression we could additionally predict the severity of negative symptoms from ventral striatal activation patterns. These results show that MVPA can be used to substantially increase the accuracy of diagnostic classification on the basis of task-related fMRI signal patterns in a regionally specific way.
Understanding the rapidly developing building blocks of speech perception in infancy requires a close look at the auditory prerequisites for speech sound processing. Pioneering studies have ...demonstrated that hemispheric specializations for language processing are already present in early infancy. However, whether these computational asymmetries can be considered a function of linguistic attributes or a consequence of basic temporal signal properties is under debate. Several studies in adults link hemispheric specialization for certain aspects of speech perception to an asymmetry in cortical tuning and reveal that the auditory cortices are differentially sensitive to spectrotemporal features of speech. Applying concurrent electrophysiological (EEG) and hemodynamic (near-infrared spectroscopy) recording to newborn infants listening to temporally structured nonspeech signals, we provide evidence that newborns process nonlinguistic acoustic stimuli that share critical temporal features with language in a differential manner. The newborn brain preferentially processes temporal modulations especially relevant for phoneme perception. In line with multi-time-resolution conceptions, modulations on the time scale of phonemes elicit strong bilateral cortical responses. Our data furthermore suggest that responses to slow acoustic modulations are lateralized to the right hemisphere. That is, the newborn auditory cortex is sensitive to the temporal structure of the auditory input and shows an emerging tendency for functional asymmetry. Hence, our findings support the hypothesis that development of speech perception is linked to basic capacities in auditory processing. From birth, the brain is tuned to critical temporal properties of linguistic signals to facilitate one of the major needs of humans: to communicate.
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