TY - JOUR AB - The synaptotrophic hypothesis posits that synapse formation stabilizes dendritic branches, yet this hypothesis has not been causally tested in vivo in the mammalian brain. Presynaptic ligand cerebellin-1 (Cbln1) and postsynaptic receptor GluD2 mediate synaptogenesis between granule cells and Purkinje cells in the molecular layer of the cerebellar cortex. Here we show that sparse but not global knockout of GluD2 causes under-elaboration of Purkinje cell dendrites in the deep molecular layer and overelaboration in the superficial molecular layer. Developmental, overexpression, structure-function, and genetic epistasis analyses indicate that dendrite morphogenesis defects result from competitive synaptogenesis in a Cbln1/GluD2-dependent manner. A generative model of dendritic growth based on competitive synaptogenesis largely recapitulates GluD2 sparse and global knockout phenotypes. Our results support the synaptotrophic hypothesis at initial stages of dendrite development, suggest a second mode in which cumulative synapse formation inhibits further dendrite growth, and highlight the importance of competition in dendrite morphogenesis. AU - Takeo, Yukari H. AU - Shuster, S. Andrew AU - Jiang, Linnie AU - Hu, Miley AU - Luginbuhl, David J. AU - Rülicke, Thomas AU - Contreras, Ximena AU - Hippenmeyer, Simon AU - Wagner, Mark J. AU - Ganguli, Surya AU - Luo, Liqun ID - 8544 IS - 4 JF - Neuron TI - GluD2- and Cbln1-mediated competitive synaptogenesis shapes the dendritic arbors of cerebellar Purkinje cells VL - 109 ER - TY - THES AB - The brain is one of the largest and most complex organs and it is composed of billions of neurons that communicate together enabling e.g. consciousness. The cerebral cortex is the largest site of neural integration in the central nervous system. Concerted radial migration of newly born cortical projection neurons, from their birthplace to their final position, is a key step in the assembly of the cerebral cortex. The cellular and molecular mechanisms regulating radial neuronal migration in vivo are however still unclear. Recent evidence suggests that distinct signaling cues act cell-autonomously but differentially at certain steps during the overall migration process. Moreover, functional analysis of genetic mosaics (mutant neurons present in wild-type/heterozygote environment) using the MADM (Mosaic Analysis with Double Markers) analyses in comparison to global knockout also indicate a significant degree of non-cell-autonomous and/or community effects in the control of cortical neuron migration. The interactions of cell-intrinsic (cell-autonomous) and cell-extrinsic (non-cell-autonomous) components are largely unknown. In part of this thesis work we established a MADM-based experimental strategy for the quantitative analysis of cell-autonomous gene function versus non-cell-autonomous and/or community effects. The direct comparison of mutant neurons from the genetic mosaic (cell-autonomous) to mutant neurons in the conditional and/or global knockout (cell-autonomous + non-cell-autonomous) allows to quantitatively analyze non-cell-autonomous effects. Such analysis enable the high-resolution analysis of projection neuron migration dynamics in distinct environments with concomitant isolation of genomic and proteomic profiles. Using these experimental paradigms and in combination with computational modeling we show and characterize the nature of non-cell-autonomous effects to coordinate radial neuron migration. Furthermore, this thesis discusses recent developments in neurodevelopment with focus on neuronal polarization and non-cell-autonomous mechanisms in neuronal migration. AU - Hansen, Andi H ID - 9962 KW - Neuronal migration KW - Non-cell-autonomous KW - Cell-autonomous KW - Neurodevelopmental disease SN - 2663-337X TI - Cell-autonomous gene function and non-cell-autonomous effects in radial projection neuron migration ER - TY - JOUR AB - Scientific research is to date largely restricted to wealthy laboratories in developed nations due to the necessity of complex and expensive equipment. This inequality limits the capacity of science to be used as a diplomatic channel. Maker movements use open-source technologies including additive manufacturing (3D printing) and laser cutting, together with low-cost computers for developing novel products. This movement is setting the groundwork for a revolution, allowing scientific equipment to be sourced at a fraction of the cost and has the potential to increase the availability of equipment for scientists around the world. Science education is increasingly recognized as another channel for science diplomacy. In this perspective, we introduce the idea that the Maker movement and open-source technologies have the potential to revolutionize science, technology, engineering and mathematics (STEM) education worldwide. We present an open-source STEM didactic tool called SCOPES (Sparking Curiosity through Open-source Platforms in Education and Science). SCOPES is self-contained, independent of local resources, and cost-effective. SCOPES can be adapted to communicate complex subjects from genetics to neurobiology, perform real-world biological experiments and explore digitized scientific samples. We envision such platforms will enhance science diplomacy by providing a means for scientists to share their findings with classrooms and for educators to incorporate didactic concepts into STEM lessons. By providing students the opportunity to design, perform, and share scientific experiments, students also experience firsthand the benefits of a multinational scientific community. We provide instructions on how to build and use SCOPES on our webpage: http://scopeseducation.org. AU - Beattie, Robert J AU - Hippenmeyer, Simon AU - Pauler, Florian ID - 7814 JF - Frontiers in Education SN - 2504-284X TI - SCOPES: Sparking curiosity through Open-Source platforms in education and science VL - 5 ER - TY - GEN AB - The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal in vivo imaging, we reported that a substantial proportion of blood vessels in the adult brain sporadically occluded and regressed. Their regression proceeded through sequential stages of blood-flow occlusion, endothelial cell collapse, relocation or loss of pericytes, and retraction of glial endfeet. Regressing vessels were found to be widespread in mouse, monkey and human brains. Both brief occlusions of the middle cerebral artery and lipopolysaccharide-mediated inflammation induced an increase of vessel regression. Blockage of leukocyte adhesion to endothelial cells alleviated LPS-induced vessel regression. We further revealed that blood vessel regression caused a reduction of neuronal activity due to a dysfunction in mitochondrial metabolism and glutamate production. Our results elucidate the mechanism of vessel regression and its role in neuronal function in the adult brain. AU - Gao, Xiaofei AU - Li, Jun-Liszt AU - Chen, Xingjun AU - Ci, Bo AU - Chen, Fei AU - Lu, Nannan AU - Shen, Bo AU - Zheng, Lijun AU - Jia, Jie-Min AU - Yi, Yating AU - Zhang, Shiwen AU - Shi, Ying-Chao AU - Shi, Kaibin AU - Propson, Nicholas E AU - Huang, Yubin AU - Poinsatte, Katherine AU - Zhang, Zhaohuan AU - Yue, Yuanlei AU - Bosco, Dale B AU - Lu, Ying-mei AU - Yang, Shi-bing AU - Adams, Ralf H. AU - Lindner, Volkhard AU - Huang, Fen AU - Wu, Long-Jun AU - Zheng, Hui AU - Han, Feng AU - Hippenmeyer, Simon AU - Stowe, Ann M. AU - Peng, Bo AU - Margeta, Marta AU - Wang, Xiaoqun AU - Liu, Qiang AU - Körbelin, Jakob AU - Trepel, Martin AU - Lu, Hui AU - Zhou, Bo O. AU - Zhao, Hu AU - Su, Wenzhi AU - Bachoo, Robert M. AU - Ge, Woo-ping ID - 8616 T2 - bioRxiv TI - Reduction of neuronal activity mediated by blood-vessel regression in the brain ER - TY - JOUR AB - Mosaic analysis with double markers (MADM) technology enables concomitant fluorescent cell labeling and induction of uniparental chromosome disomy (UPD) with single-cell resolution. In UPD, imprinted genes are either overexpressed 2-fold or are not expressed. Here, the MADM platform is utilized to probe imprinting phenotypes at the transcriptional level. This protocol highlights major steps for the generation and isolation of projection neurons and astrocytes with MADM-induced UPD from mouse cerebral cortex for downstream single-cell and low-input sample RNA-sequencing experiments. For complete details on the use and execution of this protocol, please refer to Laukoter et al. (2020b). AU - Laukoter, Susanne AU - Amberg, Nicole AU - Pauler, Florian AU - Hippenmeyer, Simon ID - 8978 IS - 3 JF - STAR Protocols SN - 2666-1667 TI - Generation and isolation of single cells from mouse brain with mosaic analysis with double markers-induced uniparental chromosome disomy VL - 1 ER -