UPF1 regulates mRNA stability by sensing poorly translated coding sequences.

Post-transcriptional mRNA regulation shapes gene expression, yet how cis-elements and mRNA translation interface to regulate mRNA stability is poorly understood. We find that the strength of translation initiation, upstream open reading frame (uORF) content, codon optimality, AU-rich elements, microRNA binding sites, and open reading frame (ORF) length function combinatorially to regulate mRNA stability. Machine-learning analysis identifies ORF length as the most important conserved feature regulating mRNA decay.

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1 mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals).

A Neutrophil Timer Coordinates Immune Defense and Vascular Protection.

Neutrophils eliminate pathogens efficiently but can inflict severe damage to the host if they over-activate within blood vessels. It is unclear how immunity solves the dilemma of mounting an efficient anti-microbial defense while preserving vascular health. Here, we identify a neutrophil-intrinsic program that enabled both.

Neutrophils instruct homeostatic and pathological states in naive tissues.

Immune protection relies on the capacity of neutrophils to infiltrate challenged tissues. Naive tissues, in contrast, are believed to remain free of these cells and protected from their toxic cargo. Here, we show that neutrophils are endowed with the capacity to infiltrate multiple tissues in the steady-state, a process that follows tissue-specific dynamics.

The crux of Cux genes in neuronal function and plasticity.

Cux1 and Cux2 are the vertebrate members of a family of homeodomain transcription factors (TF) containing Cut repeat DNA-binding sequences. Perturbation of their expression has been implicated in a wide variety of diseases and disorders, ranging from cancer to autism spectrum disorder (ASD). Within the nervous system, both genes are expressed during neurogenesis and in specific neuronal subpopulations.

IGF-1 receptor regulates dynamic changes in neuronal polarity during cerebral cortical migration.

During cortical development, neurons undergo polarization, oriented migration and layer-type differentiation. The biological and biochemical mechanisms underlying these processes are not completely understood. In neurons in culture we showed that IGF-1 receptor activation is important for growth cone assembly and axonal formation.

Cux1 Enables Interhemispheric Connections of Layer II/III Neurons by Regulating Kv1-Dependent Firing.

Neuronal subtype-specific transcription factors (TFs) instruct key features of neuronal function and connectivity. Activity-dependent mechanisms also contribute to wiring and circuit assembly, but whether and how they relate to TF-directed neuronal differentiation is poorly investigated. Here we demonstrate that the TF Cux1 controls the formation of the layer II/III corpus callosum (CC) projections through the developmental transcriptional regulation of Kv1 voltage-dependent potassium channels and the resulting postnatal switch to a Kv1-dependent firing mode.

Sex Hormones Coordinate Neutrophil Immunity in the Vagina by Controlling Chemokine Gradients.

Estradiol-based contraceptives and hormonal replacement therapy predispose women to Candida albicans infections. Moreover, during the ovulatory phase (high estradiol), neutrophil numbers decrease in the vaginal lumen and increase during the luteal phase (high progesterone). Vaginal secretions contain chemokines that drive neutrophil migration into the lumen.

A map of taste neuron projections in the Drosophila CNS.

We provide a map of the projections of taste neurons in the CNS of Drosophila. Using a collection of 67 GAL4 drivers representing the entire repertoire of Gr taste receptors, we systematically map the projections of neurons expressing these drivers in the thoracico-abdominal ganglion and the suboesophageal ganglion (SOG). We define 9 categories of projections in the thoracico-abdominal ganglia and 10 categories in the SOG.

Brief report: reduced expression of CD18 leads to the in vivo expansion of hematopoietic stem cells in mouse bone marrow.

Leukocyte adhesion deficiency type-I is a primary immunodeficiency caused by mutations in the ITGB2 gene (CD18 leukocyte integrin) which lead to defects in leukocyte extravasation. To investigate the role of CD18 in hematopoietic stem cell (HSC) biology, we have thoroughly characterized the HSCs of CD18 Itgb2(tm1bay) hypomorphic mice (CD18(HYP) ) both by flow cytometry and using in vitro and in vivo transplantation assays. Flow cytometry analyses and cultures in methyl cellulose revealed that bone marrow (BM) from CD18(HYP) mice was enriched in hematopoietic precursors, mainly early quiescent short-term and long-term Hematopoietic progenitors cells.

The molecular and cellular basis of taste coding in the legs of Drosophila.

To understand the principles of taste coding, it is necessary to understand the functional organization of the taste organs. Although the labellum of the Drosophila melanogaster head has been described in detail, the tarsal segments of the legs, which collectively contain more taste sensilla than the labellum, have received much less attention. We performed a systematic anatomical, physiological, and molecular analysis of the tarsal sensilla of Drosophila.

Innate immune cells as homeostatic regulators of the hematopoietic niche.

Two cellular systems of paramount importance for mammalian physiology, the myeloid and the hematopoietic, have received a great deal of attention in the past decade. Myeloid leukocytes, classically involved in mediating innate immune responses, are now known to regulate other important aspects of the organism's physiology, from development to regulation of metabolic functions. In parallel, many diverse cellular and molecular components have been identified in the bone marrow (BM) that are required for the regulation and lifelong preservation of hematopoietic stem and progenitor cells (HSPC).

Rhythmic modulation of the hematopoietic niche through neutrophil clearance.

Unique among leukocytes, neutrophils follow daily cycles of release from and migration back into the bone marrow, where they are eliminated. Because removal of dying cells generates homeostatic signals, we explored whether neutrophil elimination triggers circadian events in the steady state. Here, we report that the homeostatic clearance of neutrophils provides cues that modulate the physiology of the bone marrow.

Molecular and cellular organization of the taste system in the Drosophila larva.

We examine the molecular and cellular basis of taste perception in the Drosophila larva through a comprehensive analysis of the expression patterns of all 68 Gustatory receptors (Grs). Gr-GAL4 lines representing each Gr are examined, and 39 show expression in taste organs of the larval head, including the terminal organ (TO), the dorsal organ (DO), and the pharyngeal organs. A receptor-to-neuron map is constructed.

The molecular and cellular basis of bitter taste in Drosophila.

The extent of diversity among bitter-sensing neurons is a fundamental issue in the field of taste. Data are limited and conflicting as to whether bitter neurons are broadly tuned and uniform, resulting in indiscriminate avoidance of bitter stimuli, or diverse, allowing a more discerning evaluation of food sources. We provide a systematic analysis of how bitter taste is encoded by the major taste organ of the Drosophila head, the labellum.

The molecular basis of CO2 reception in Drosophila.

CO(2) elicits a response from many insects, including mosquito vectors of diseases such as malaria and yellow fever, but the molecular basis of CO(2) detection is unknown in insects or other higher eukaryotes. Here we show that Gr21a and Gr63a, members of a large family of Drosophila seven-transmembrane-domain chemoreceptor genes, are coexpressed in chemosensory neurons of both the larva and the adult. The two genes confer CO(2) response when coexpressed in an in vivo expression system, the "empty neuron system.

The integrin alphaMbeta2 anchors hematopoietic progenitors in the bone marrow during enforced mobilization.

The sulfated polysaccharide fucoidan can rapidly mobilize hematopoietic progenitor cells (HPCs) and long-term repopulating stem cells from the bone marrow (BM) to the circulation. While searching for mechanisms involved in this phenomenon we found that BM myeloid cells bound to fucoidan through the integrin alphaMbeta2 (macrophage antigen-1 [Mac-1]) and L-selectin resulting in alphaMbeta2-independent release of neutrophil elastase, but inhibition of elastase activity did not impair fucoidan-induced mobilization. Mobilization of HPCs by fucoidan was enhanced in animals deficient in alphaM (alphaM-/-) compared with wild-type (alphaM+/+) animals and higher plasma levels of the chemokine CXCL12/stromal cell-derived factor-1 (SDF-1) were achieved in alphaM-/- mice by fucoidan treatment.

Spatial regulation of developmental signaling by a serpin.

An extracellular serine protease cascade generates the ligand that activates the Toll signaling pathway to establish dorsoventral polarity in the Drosophila embryo. We show here that this cascade is regulated by a serpin-type serine protease inhibitor, which plays an essential role in confining Toll signaling to the ventral side of the embryo. This role is strikingly analogous to the function of the mammalian serpin antithrombin in localizing the blood-clotting cascade, suggesting that serpin inhibition of protease activity may be a general mechanism for achieving spatial control in diverse biological processes.

Insights into leukocyte adhesion deficiency type 2 from a novel mutation in the GDP-fucose transporter gene.

Leukocyte adhesion deficiency type 2 (LADII) is characterized by defective selectin ligand formation, recurrent infection, and mental retardation. This rare syndrome has only been described in 2 kindreds of Middle Eastern descent who have differentially responded to exogenous fucose treatment. The molecular defect was recently ascribed to single and distinct missense mutations in a putative Golgi guanosine diphosphate (GDP)-fucose transporter.

Functional selectin ligands mediating human CD34(+) cell interactions with bone marrow endothelium are enhanced postnatally.

Hematopoietic progenitor cells (HPCs) can home to the bone marrow (BM) after a simple intravenous injection, but the adhesive mechanisms mediating the initial interactions of human HPCs with the BM endothelium have not been evaluated in vivo. Using fluorescence intravital microscopy and homing assays in NOD/SCID mice, we show that endothelial selectins are necessary for human adult CD34(+) cell homing, since rolling on BM endothelium and retention in the BM compartment are drastically reduced (>90%) in endothelial selectin-deficient NOD/SCID mice. Comparative analyses of CD34(+) cells collected from adults and from cord blood (CB) reveal that neonatal cells display reduced rolling fractions compared with adult CD34(+) cells obtained from peripheral blood or BM, suggesting abnormal selectin ligand function on neonatal progenitors.

Primary role for adherent leukocytes in sickle cell vascular occlusion: a new paradigm.

Vascular occlusion is the major cause of morbidity and mortality in sickle cell disease but its mechanisms are poorly understood. We demonstrate by using intravital microscopy in mice expressing human sickle hemoglobin (SS) that SS red blood cells (RBCs) bind to adherent leukocytes in inflamed venules, producing vasoocclusion of cremasteric venules. SS mice deficient in P- and E-selectins, which display defective leukocyte recruitment to the vessel wall, are protected from vasoocclusion.