Project description:At birth, newborns are exposed to gut microbiota, which plays a critical role in host physiology. A reduced level of microbial diversity has been associated with necrotizing enterocolitis (NEC), one of the most deadly diseases in premature infants, but the underlying disease mechanisms are still poorly understood. Although the epithelial turnover of germ free mice is significantly delayed compared to conventionally raised mice, it remains unclear how gut microbiota exposure in the early postnatal period promotes stem cell renewal and differentiation. By analyzing genetic and experimental mouse models and performing single cell analysis, we demonstrate that gut microbiota promotes stem cell differentiation through the activation of critical stromal niche components. Our single cell analysis reveals that gut microbiota controls the size and heterogeneity of macrophage populations that secrete Wnt ligands, thereby maintaining the proliferation of intestinal telocytes, a recently identified gut mesenchymal stem cell niche. We show that stem cell differentiation, when impaired by antibiotic treatment promotes NEC, while treatment with Lactobacillus, which in NEC is dramatically less abundant, rescues NEC-like pathology through the activation of macrophage and telocyte niches. Our work highlights the mechanisms of how gut microbiota-facilitate mesenchymal niche proliferation which supports stem cell differentiation in early postnatal development.
Project description:During early postnatal development, hippocampal circuits are assembled through the coordinated navigation of axonal growth cones toward their synaptic targets. While growth cones are known to rely on local proteomic changes to interpret guidance cues, the developmental dynamics of their proteomic composition remain poorly understood. We performed a systematic proteomic characterization of growth cones isolated from whole Hippocampus or Dentate gyrus tissue at postnatal day (P) 1, 3, and 5 from wildtype animals. Our analysis showed that at P1 growth cones of both tissues have a common proteomic signature. While hippocampal growth cones undergo a rapid transition from exploratory to a more mature state until P5, growth cones of the Dentate Gyrus maintain their exploratory profile in the same time frame suggesting a delayed maturation. Growth cones of the Hippocampus and Dentate Gyrus are characterized by several temporally regulated proteins, reflecting their dynamicity and different developmental trajectories.
Project description:Long noncoding RNAs (lncRNAs) display pervasive expression and function in the developing nervous system. Temporal profiling of gene expression in the retina has demonstrated differential expression of lncRNAs throughout development, however determinations of lncRNA function during retinal development remain limited. In this study, we identify numerous lncRNAs with dynamic temporal expression and characterize the function of the lncRNA Gm11454, which we have named Peanut. Using an overexpression model in mice, we determine that Peanut promotes rod photoreceptor fate and neurogenesis of retinal progenitor cells (RPCs) via inhibition of Notch signaling and regulating expression of neighboring gene Tox2. A novel Peanut knockout mouse model demonstrates that Peanut is required for proper visual function and photoreceptor gene expression. Finally, we determined that Peanut is necessary for proper cell cycle progression and neurogenesis. Our results characterize the function of a novel lncRNA as a regulator of RPC neurogenesis and differentiation and support the importance of lncRNAs in the developing retina.