Neural control of maternal and paternal behaviors Dulac, Catherine; O’Connell, Lauren A.; Wu, Zheng
Science (American Association for the Advancement of Science),
08/2014, Volume:
345, Issue:
6198
Journal Article
Peer reviewed
Open access
Parental care, including feeding and protection of young, is essential for the survival as well as mental and physical well-being of the offspring. A large variety of parental behaviors has been ...described across species and sexes, raising fascinating questions about how animals identify the young and how brain circuits drive and modulate parental displays in males and females. Recent studies have begun to uncover a striking antagonistic interplay between brain systems underlying parental care and infant-directed aggression in both males and females, as well as a large range of intrinsic and environmentally driven neural modulation and plasticity. Improved understanding of the neural control of parental interactions in animals should provide novel insights into the complex issue of human parental care in both health and disease.
RNA decay is vital for regulating mRNA abundance and gene expression. Existing technologies lack the spatiotemporal precision or transcript specificity to capture the stochastic and transient decay ...process. We devise a general strategy to inducibly recruit protein factors to modulate target RNA metabolism. Specifically, we introduce a Rapid Inducible Decay of RNA (RIDR) technology to degrade target mRNAs within minutes. The fast and synchronous induction enables direct visualization of mRNA decay dynamics in cells. Applying RIDR to endogenous ACTB mRNA reveals rapid formation and dissolution of RNA granules in pre-existing P-bodies. Time-resolved RNA distribution measurements demonstrate rapid RNA decay inside P-bodies, which is further supported by knocking down P-body constituent proteins. Light and oxidative stress modulate P-body behavior, potentially reconciling the contradictory literature about P-body function. This study reveals compartmentalized RNA decay kinetics, establishing RIDR as a pivotal tool for exploring the spatiotemporal RNA metabolism in cells.
Mutations in gene regulatory elements have been associated with a wide range of complex neuropsychiatric disorders. However, due to their cell-type specificity and difficulties in characterizing ...their regulatory targets, the ability to identify causal genetic variants has remained limited. To address these constraints, we perform an integrative analysis of chromatin interactions, open chromatin regions and transcriptomes using promoter capture Hi-C, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and RNA sequencing, respectively, in four functionally distinct neural cell types: induced pluripotent stem cell (iPSC)-induced excitatory neurons and lower motor neurons, iPSC-derived hippocampal dentate gyrus-like neurons and primary astrocytes. We identify hundreds of thousands of long-range cis-interactions between promoters and distal promoter-interacting regions, enabling us to link regulatory elements to their target genes and reveal putative processes that are dysregulated in disease. Finally, we validate several promoter-interacting regions by using clustered regularly interspaced short palindromic repeats (CRISPR) techniques in human excitatory neurons, demonstrating that CDK5RAP3, STRAP and DRD2 are transcriptionally regulated by physically linked enhancers.
SARS-CoV-2 can cause acute respiratory distress and death in some patients
. Although severe COVID-19 is linked to substantial inflammation, how SARS-CoV-2 triggers inflammation is not clear
. ...Monocytes and macrophages are sentinel cells that sense invasive infection to form inflammasomes that activate caspase-1 and gasdermin D, leading to inflammatory death (pyroptosis) and the release of potent inflammatory mediators
. Here we show that about 6% of blood monocytes of patients with COVID-19 are infected with SARS-CoV-2. Monocyte infection depends on the uptake of antibody-opsonized virus by Fcγ receptors. The plasma of vaccine recipients does not promote antibody-dependent monocyte infection. SARS-CoV-2 begins to replicate in monocytes, but infection is aborted, and infectious virus is not detected in the supernatants of cultures of infected monocytes. Instead, infected cells undergo pyroptosis mediated by activation of NLRP3 and AIM2 inflammasomes, caspase-1 and gasdermin D. Moreover, tissue-resident macrophages, but not infected epithelial and endothelial cells, from lung autopsies from patients with COVID-19 have activated inflammasomes. Taken together, these findings suggest that antibody-mediated SARS-CoV-2 uptake by monocytes and macrophages triggers inflammatory cell death that aborts the production of infectious virus but causes systemic inflammation that contributes to COVID-19 pathogenesis.
Translation is regulated spatiotemporally to direct protein synthesis when and where it is needed. RNA localization and local translation have been observed in various subcellular compartments, ...allowing cells to rapidly and finely adjust their proteome post-transcriptionally. Local translation on membrane-bound organelles is important to efficiently synthesize proteins targeted to the organelles. Protein-RNA phase condensates restrict RNA spatially in membraneless organelles and play essential roles in translation regulation and RNA metabolism. In addition, the temporal translation kinetics not only determine the amount of protein produced, but also serve as an important checkpoint for the quality of ribosomes, mRNAs, and nascent proteins. Translation imaging provides a unique capability to study these fundamental processes in the native environment. Recent breakthroughs in imaging enabled real-time visualization of translation of single mRNAs, making it possible to determine the spatial distribution and key biochemical parameters of in vivo translation dynamics. Here we reviewed the recent advances in translation imaging methods and their applications to study spatiotemporal translation regulation in vivo.
A deletion or duplication in the 16p11.2 region is associated with neurodevelopmental disorders, including autism spectrum disorder and schizophrenia. In addition to clinical characteristics, ...carriers of the 16p11.2 copy-number variant (CNV) manifest opposing neuroanatomical phenotypes—e.g., macrocephaly in deletion carriers (16pdel) and microcephaly in duplication carriers (16pdup). Using fibroblasts obtained from 16pdel and 16pdup carriers, we generated induced pluripotent stem cells (iPSCs) and differentiated them into neurons to identify causal cellular mechanisms underlying neurobiological phenotypes. Our study revealed increased soma size and dendrite length in 16pdel neurons and reduced neuronal size and dendrite length in 16pdup neurons. The functional properties of iPSC-derived neurons corroborated aspects of these contrasting morphological differences that may underlie brain size. Interestingly, both 16pdel and 16pdup neurons displayed reduced synaptic density, suggesting that distinct mechanisms may underlie brain size and neuronal connectivity at this locus.
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•Cellular model of NDDs established using hiPSCs from 16pdel and 16pdup carriers•Opposing neuronal size phenotype may model macro- and microcephaly•Synaptic impairment in 16pdel and 16pdup neurons may reflect behavioral features•Functional compensation observed in 16pdup compared with 16pdel neurons
Deshpande et al. show that neurons derived from individuals harboring neurodevelopmental disorders caused by the 16p11.2 deletion or duplication manifest contrasting cellular phenotypes that may underlie the macro- or microcephaly observed in carriers, respectively. Comparable functional changes in deletion- and duplication-derived neurons suggest similar mechanisms underlying common clinical features, like autism.
In structure-based virtual screening, compound ranking through a consensus of scores from a variety of docking programs or scoring functions, rather than ranking by scores from a single program, ...provides better predictive performance and reduces target performance variability. Here we compare traditional consensus scoring methods with a novel, unsupervised gradient boosting approach. We also observed increased score variation among active ligands and developed a statistical mixture model consensus score based on combining score means and variances. To evaluate performance, we used the common performance metrics ROCAUC and EF1 on 21 benchmark targets from DUD-E. Traditional consensus methods, such as taking the mean of quantile normalized docking scores, outperformed individual docking methods and are more robust to target variation. The mixture model and gradient boosting provided further improvements over the traditional consensus methods. These methods are readily applicable to new targets in academic research and overcome the potentially poor performance of using a single docking method on a new target.
Planar cell polarity (PCP) signaling plays a fundamental role in shaping the development and ongoing function of the nervous system, beginning from early stages of neural tube closure and spanning ...the maintenance of functional synapses in adults. While mutations in core PCP signaling proteins have long been suspected to underlie neural tube closure defects in humans, recent findings also implicate their potential involvement in neurodevelopmental and neuropsychiatric disorders. Missense and loss-of-function mutations in CELSR3, a core component of PCP signaling complexes, are highly associated with Tourette Disorder. Although the functional significance of these mutations has yet to be elucidated in animal and cell models, the expression patterns of Celsr3 in mice point to alterations in cortico-striato-thalamo-cortical circuits. Here, we briefly review the known functions of Celsr3 for nervous system development. We also propose circuit models for Tourette Disorder by hypothesizing roles for Celsr3 in controlling striatal neuromodulation via effects on cholinergic interneurons, and thalamic inhibition through its functions in thalamic reticular nuclei. Testing these and related hypotheses in animal and cell models will move us closer to unraveling the neuropathogenesis of Tourette Disorder, with the ultimate goal of developing more efficacious treatments for both motor and cognitive symptoms.
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Background & Aims Core 1– and core 3–derived mucin-type O-linked oligosaccharides (O-glycans) are major components of the colonic mucus layer. Defective forms of colonic O-glycans, such as Tn ...antigen, frequently are observed in patients with ulcerative colitis and colorectal cancer, but it is not clear if they contribute to pathogenesis. We investigated whether and how impaired O-glycosylation contributes to the development of colitis-associated colorectal cancer using mice lacking intestinal core 1– and core 3–derived O -glycans. Methods We generated mice that lack the core 1– and core 3–derived intestinal O-glycans (DKO mice) and analyzed them, along with mice that lack the intestinal epithelial core 1 O-glycans (IEC C1galt1 - /- mice) or mice that lack core 3 O-glycans (C3 Gnt-/- mice). Intestinal tissues were collected at different time points and analyzed for levels of mucin and Tn antigen, development of colitis, and tumor formation using imaging, quantitative polymerase chain reaction, immunoblot, and enzyme-linked immunosorbent assay techniques. We also used cellular and genetic approaches, as well as intestinal microbiota depletion, to identify inflammatory mediators and pathways that contribute to disease in DKO and wild-type littermates (controls). Results Intestinal tissues from DKO mice contained higher levels of Tn antigen and had more severe spontaneous chronic colitis than tissues from intestinal epithelial cell (IEC) C1galt1 - /- mice, whereas spontaneous colitis was absent in C3GnT - /- and control mice. IEC C1galt1 - /- mice and DKO mice developed spontaneous colorectal tumors, although the onset of tumors in the DKO mice occurred earlier (age, 8–9 mo) than that in IEC C1galt1 -/- mice (approximately age 12 months). Antibiotic depletion of the microbiota did not cause loss of Tn antigen but did reduce the development of colitis and cancer formation in DKO mice. Colon tissues from DKO mice, but not control mice, contained active forms of caspase 1 and increased caspase 11, which were reduced after antibiotic administration. Supernatants from colon tissues of DKO mice contained increased levels of interleukin-1β and interleukin-18, compared with those from control mice. Disruption of the caspase 1 and caspase 11 genes in DKO mice (DKO/ Casp 1/11 - /- mice) decreased the development of colitis, characterized by reduced colonic thickening, hyperplasia, and inflammatory infiltrate, compared with DKO mice. Conclusions Impaired expression of O-glycans causes colonic mucus barrier breach and subsequent microbiota-mediated activation of caspase 1–dependent inflammasomes in colonic epithelial cells of mice. These processes could contribute to colitis-associated colon cancer in human beings.
mRNA translation and its regulation shape the human proteome. Lyon et al. (2019) and Boersma et al. (2019) introduce new orthogonal peptide-tagging systems to study translation in multiple reading ...frames. Both groups discovered diverse translation behavior of single mRNAs derived from the same genes.
mRNA translation and its regulation shape the human proteome. Lyon et al. (2019) and Boersma et al. (2019) introduce new orthogonal peptide-tagging systems to study translation in multiple reading frames. Both groups discovered diverse translation behavior of single mRNAs derived from the same genes.
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