Biology subjects

Martin-Villalba, A.

Publications and source records attributed to Martin-Villalba, A..

7 recordsLinked to original sources

bioRxiv2018

An immune-CNS axis activates remote hippocampal stem cells following Spinal Transection Injury

External stimuli such as injury, learning, or stress influence the production of neurons by neural stem cells (NSCs) in the adult mammalian brain. These external stimuli directly impact stem cell activity by influencing areas directly connected or in close proximity to the neurogenic niches of the adult brain. However, very little is known on how distant injuries affect NSC activation state. In this study we demonstrate that a thoracic spinal transection injury activates the distally located hippocampal-NSCs. This activation leads to a transient increase production of neurons that functionally integrate to improve animals performance in hippocampal-related memory tasks. We further show that interferon-CD95 signaling is required to promote injury-mediated activation of remote NSCs. Thus, we identify an immune-CNS axis responsible for injury-mediated activation of remotely located NSCs.

neuroscience↗

bioRxiv2018

Cell-cell contact dictates life or death decisions following CD95 activation in cancer

Cancer cells react to CD95 activation with either apoptotic or tumorigenic responses. Yet, the determinants of these two antithetic reactions are fundamentally not understood. Here, we show that pre-confined CD95L molecules activate apoptosis of cancer cells in-vitro. For particular CD95L pre-confinement, apoptosis activation is most efficient. Surprisingly, in tumor models, the same pre-confinement yields enhanced proliferation of cancer cells. This shift is rooted in cell-cell interactions, as proliferation was also observed in tumorspheres in-vitro. Indeed, proliferation required death-domain tyrosine phosphorylation of CD95 that was facilitated by cell-cell contacts, whereas decreasing the levels of global tyrosine kinase activity favored apoptosis. Altogether, the response to CD95 activation is cell context-dependent and tunable by CD95L pre-confinement, thereby opening therapeutic opportunities in cancer.\n\nOne Sentence SummaryCell-cell contact tunes tyrosine-kinase activity thereby dictating life or death upon CD95 activation by pre-confined CD95L.

cancer biology↗

bioRxiv2018

Onset of differentiation is posttranscriptionally controlled in adult neural stem cells

The contribution of posttranscriptional regulation of gene expression to neural stem cell differentiation during tissue homeostasis remains elusive. Here we show highly dynamic changes in protein synthesis along differentiation of stem cells to neurons in vivo. Examination of individual transcripts using RiboTag mouse models reveals that neural stem cells efficiently translate abundant transcripts, whereas translation becomes increasingly controlled with the onset of differentiation. Stem cell generation of early neuroblasts involves translational repression of a subset of mRNAs including the stem cell-identity factors Sox2 and Pax6 as well as translation machinery components. In silico motif analysis identifies a pyrimidine-rich motif (PRM) in this repressed subset. A drop in mTORC1 activity at the onset of differentiation selectively blocks translation of PRM-containing transcripts. Our data uncovers how a drop in mTORC1 allows robust simultaneous posttranscriptional repression of key stem cell identity-factors and translation-components and thereby stemness exit and migration.

neuroscience↗

bioRxiv2017

Analysis of LRRC45 indicates cooperative functions of distal appendages at early steps of ciliogenesis

Cilia perform essential signalling functions during development and tissue homeostasis. Ciliary malfunction causes a variety of diseases, named ciliopathies. The key role that the mother centriole plays in cilia formation can be attributed to appendage proteins that associate exclusively with the mother centriole. The distal appendages form a platform that docks early ciliary vesicles and removes CP110/Cep97 inhibitory complexes from the mother centriole. Here, we analysed the role played by LRRC45 in appendage formation and ciliogenesis. We show that the core appendage proteins Cep83 and SCLT1 recruit LRRC45 to the mother centriole. Once there LRRC45 recruits FBF1. The association of LRRC45 with the basal body of primary and motile cilia in differentiated and stem cells reveals a broad function in ciliogenesis. In contrast to the appendage components Cep164 and Cep123, LRRC45 was neither essential for docking of early ciliary vesicles nor for removal of CP110. Rather, LRRC45 promotes cilia biogenesis in CP110-uncapped centrioles by organising centriolar satellites and promoting the docking of Rab8 GTPase-positive vesicles. We propose that, instead of acting solely as a platform to recruit early vesicles, centriole appendages form discrete scaffolds of cooperating proteins that execute specific functions that promote the initial steps of ciliogenesis.

cell biology↗

bioRxiv2017

Post-transcriptional regulation of adult CNS axonal regeneration by Cpeb1

Adult mammalian CNS neurons are unable to regenerate following axonal injury, leading to permanent functional impairments. Yet, the reasons underlying this regeneration failure are not fully understood. Here, we study the transcriptome and proteome shortly after spinal cord injury. Profiling of the total and ribosome-bound RNA in injured and naive spinal cords identify a substantial post-transcriptional regulation of gene expression. In particular, transcripts associated with nervous system development were downregulated in the total RNA-fraction while remaining stably loaded onto ribosomes. Interestingly, motif association analysis of post-transcriptionally regulated transcripts identified the cytoplasmic polyadenylation element (CPE) as enriched in a subset of these transcripts that was more resistant to injury-induced reduction at transcriptome level. Modulation of these transcripts by overexpression of the CPE binding protein, Cpeb1, in mouse and Drosophila CNS neurons promoted axonal regeneration following injury. Our study uncovers a global conserved post-transcriptional mechanism enhancing regeneration of injured CNS axons.

neuroscience↗

bioRxiv2017

Revealing Age-Related Changes of Adult Hippocampal Neurogenesis

In the adult hippocampus, neural stem cells (NSCs) continuously produce new neurons that integrate into the neuronal network to modulate learning and memory. The amount and quality of newly generated neurons decline with age, which can be counteracted by increasing intrinsic Wnt activity in NSCs. However, the precise cellular changes underlying this age-related decline or its rescue through Wnt remain unclear. The present study combines development of a mathematical model and experimental data to address features controlling stem cell dynamics. We show that available experimental data fit a model in which quiescent NSCs can either become activated to divide or undergo depletion events, consisting of astrocytic transformation and apoptosis. Additionally, we demonstrate that aged NSCs remain longer in quiescence and have a higher probability to become re-activated versus being depleted. Finally, our model explains that high NSC-Wnt activity leads to longer time in quiescence while augmenting the probability of activation.

systems biology↗

bioRxiv2016

RNA-seq library preparation from single pancreatic acinar cells

Single cell RNA sequencing technology has emerged as a promising tool to uncover previously neglected cellular heterogeneity. Multiple methods and protocols have been developed to apply single cell sequencing to different cell types from various organs. However, library preparation for RNA sequencing remains challenging for cell types with high RNAse content due to rapid degradation of endogenous RNA molecules upon cell lysis. To this end, we developed a protocol based on the SMART-seq2 technology for single cell RNA sequencing of pancreatic acinar cells, the cell type with one of the highest ribonuclease concentration measured to date. This protocol reliably produces high quality libraries from single acinar cells reaching a total of 5x106 reads / cell and [~] 80% transcript mapping rate with no detectable 3{acute}end bias. Thus, our protocol makes single cell transcriptomics accessible to cell type with very high RNAse content.

genomics↗