@article{14683,
  abstract     = {Mosaic analysis with double markers (MADM) technology enables the generation of genetic mosaic tissue in mice and high-resolution phenotyping at the individual cell level. Here, we present a protocol for isolating MADM-labeled cells with high yield for downstream molecular analyses using fluorescence-activated cell sorting (FACS). We describe steps for generating MADM-labeled mice, perfusion, single-cell suspension, and debris removal. We then detail procedures for cell sorting by FACS and downstream analysis. This protocol is suitable for embryonic to adult mice.
For complete details on the use and execution of this protocol, please refer to Contreras et al. (2021).1},
  author       = {Amberg, Nicole and Cheung, Giselle T and Hippenmeyer, Simon},
  issn         = {2666-1667},
  journal      = {STAR Protocols},
  keywords     = {General Immunology and Microbiology, General Biochemistry, Genetics and Molecular Biology, General Neuroscience},
  number       = {1},
  publisher    = {Elsevier},
  title        = {{Protocol for sorting cells from mouse brains labeled with mosaic analysis with double markers by flow cytometry}},
  doi          = {10.1016/j.xpro.2023.102771},
  volume       = {5},
  year         = {2023},
}

@article{12679,
  abstract     = {How to generate a brain of correct size and with appropriate cell-type diversity during development is a major question in Neuroscience. In the developing neocortex, radial glial progenitor (RGP) cells are the main neural stem cells that produce cortical excitatory projection neurons, glial cells, and establish the prospective postnatal stem cell niche in the lateral ventricles. RGPs follow a tightly orchestrated developmental program that when disrupted can result in severe cortical malformations such as microcephaly and megalencephaly. The precise cellular and molecular mechanisms instructing faithful RGP lineage progression are however not well understood. This review will summarize recent conceptual advances that contribute to our understanding of the general principles of RGP lineage progression.},
  author       = {Hippenmeyer, Simon},
  issn         = {0959-4388},
  journal      = {Current Opinion in Neurobiology},
  keywords     = {General Neuroscience},
  number       = {4},
  publisher    = {Elsevier},
  title        = {{Principles of neural stem cell lineage progression: Insights from developing cerebral cortex}},
  doi          = {10.1016/j.conb.2023.102695},
  volume       = {79},
  year         = {2023},
}

@article{12802,
  abstract     = {Little is known about the critical metabolic changes that neural cells have to undergo during development and how temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically essential large neutral amino acids (LNAAs), lead to autism, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different developmental stages. We found that the forebrain undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes, but what are the consequences of perturbing this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of LNAAs and lipids are interconnected in the cortex. Deletion of Slc7a5 in neurons affects the postnatal metabolic state, leading to a shift in lipid metabolism. Additionally, it causes stage- and cell-type-specific alterations in neuronal activity patterns, resulting in a long-term circuit dysfunction.},
  author       = {Knaus, Lisa and Basilico, Bernadette and Malzl, Daniel and Gerykova Bujalkova, Maria and Smogavec, Mateja and Schwarz, Lena A. and Gorkiewicz, Sarah and Amberg, Nicole and Pauler, Florian and Knittl-Frank, Christian and Tassinari, Marianna and Maulide, Nuno and Rülicke, Thomas and Menche, Jörg and Hippenmeyer, Simon and Novarino, Gaia},
  issn         = {0092-8674},
  journal      = {Cell},
  keywords     = {General Biochemistry, Genetics and Molecular Biology},
  number       = {9},
  pages        = {1950--1967.e25},
  publisher    = {Elsevier},
  title        = {{Large neutral amino acid levels tune perinatal neuronal excitability and survival}},
  doi          = {10.1016/j.cell.2023.02.037},
  volume       = {186},
  year         = {2023},
}

@article{11336,
  abstract     = {The generation of a correctly-sized cerebral cortex with all-embracing neuronal and glial cell-type diversity critically depends on faithful radial glial progenitor (RGP) cell proliferation/differentiation programs. Temporal RGP lineage progression is regulated by Polycomb Repressive Complex 2 (PRC2) and loss of PRC2 activity results in severe neurogenesis defects and microcephaly. How PRC2-dependent gene expression instructs RGP lineage progression is unknown. Here we utilize Mosaic Analysis with Double Markers (MADM)-based single cell technology and demonstrate that PRC2 is not cell-autonomously required in neurogenic RGPs but rather acts at the global tissue-wide level. Conversely, cortical astrocyte production and maturation is cell-autonomously controlled by PRC2-dependent transcriptional regulation. We thus reveal highly distinct and sequential PRC2 functions in RGP lineage progression that are dependent on complex interplays between intrinsic and tissue-wide properties. In a broader context our results imply a critical role for the genetic and cellular niche environment in neural stem cell behavior.},
  author       = {Amberg, Nicole and Pauler, Florian and Streicher, Carmen and Hippenmeyer, Simon},
  issn         = {2375-2548},
  journal      = {Science Advances},
  number       = {44},
  publisher    = {American Association for the Advancement of Science},
  title        = {{Tissue-wide genetic and cellular landscape shapes the execution of sequential PRC2 functions in neural stem cell lineage progression}},
  doi          = {10.1126/sciadv.abq1263},
  volume       = {8},
  year         = {2022},
}

@article{11449,
  abstract     = {Mutations are acquired frequently, such that each cell's genome inscribes its history of cell divisions. Common genomic alterations involve loss of heterozygosity (LOH). LOH accumulates throughout the genome, offering large encoding capacity for inferring cell lineage. Using only single-cell RNA sequencing (scRNA-seq) of mouse brain cells, we found that LOH events spanning multiple genes are revealed as tracts of monoallelically expressed, constitutionally heterozygous single-nucleotide variants (SNVs). We simultaneously inferred cell lineage and marked developmental time points based on X chromosome inactivation and the total number of LOH events while identifying cell types from gene expression patterns. Our results are consistent with progenitor cells giving rise to multiple cortical cell types through stereotyped expansion and distinct waves of neurogenesis. This type of retrospective analysis could be incorporated into scRNA-seq pipelines and, compared with experimental approaches for determining lineage in model organisms, is applicable where genetic engineering is prohibited, such as humans.},
  author       = {Anderson, Donovan J. and Pauler, Florian and Mckenna, Aaron and Shendure, Jay and Hippenmeyer, Simon and Horwitz, Marshall S.},
  issn         = {2405-4720},
  journal      = {Cell Systems},
  number       = {6},
  pages        = {438--453.e5},
  publisher    = {Elsevier},
  title        = {{Simultaneous brain cell type and lineage determined by scRNA-seq reveals stereotyped cortical development}},
  doi          = {10.1016/j.cels.2022.03.006},
  volume       = {13},
  year         = {2022},
}

@article{8544,
  abstract     = {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.},
  author       = {Takeo, Yukari H. and Shuster, S. Andrew and Jiang, Linnie and Hu, Miley and Luginbuhl, David J. and Rülicke, Thomas and Contreras, Ximena and Hippenmeyer, Simon and Wagner, Mark J. and Ganguli, Surya and Luo, Liqun},
  issn         = {1097-4199},
  journal      = {Neuron},
  number       = {4},
  pages        = {P629--644.E8},
  publisher    = {Elsevier},
  title        = {{GluD2- and Cbln1-mediated competitive synaptogenesis shapes the dendritic arbors of cerebellar Purkinje cells}},
  doi          = {10.1016/j.neuron.2020.11.028},
  volume       = {109},
  year         = {2021},
}

@article{8546,
  abstract     = {Brain neurons arise from relatively few progenitors generating an enormous diversity of neuronal types. Nonetheless, a cardinal feature of mammalian brain neurogenesis is thought to be that excitatory and inhibitory neurons derive from separate, spatially segregated progenitors. Whether bi-potential progenitors with an intrinsic capacity to generate both lineages exist and how such a fate decision may be regulated are unknown. Using cerebellar development as a model, we discover that individual progenitors can give rise to both inhibitory and excitatory lineages. Gradations of Notch activity determine the fates of the progenitors and their daughters. Daughters with the highest levels of Notch activity retain the progenitor fate, while intermediate levels of Notch activity generate inhibitory neurons, and daughters with very low levels of Notch signaling adopt the excitatory fate. Therefore, Notch-mediated binary cell fate choice is a mechanism for regulating the ratio of excitatory to inhibitory neurons from common progenitors.},
  author       = {Zhang, Tingting and Liu, Tengyuan and Mora, Natalia and Guegan, Justine and Bertrand, Mathilde and Contreras, Ximena and Hansen, Andi H and Streicher, Carmen and Anderle, Marica and Danda, Natasha and Tiberi, Luca and Hippenmeyer, Simon and Hassan, Bassem A.},
  issn         = { 22111247},
  journal      = {Cell Reports},
  number       = {10},
  publisher    = {Elsevier},
  title        = {{Generation of excitatory and inhibitory neurons from common progenitors via Notch signaling in the cerebellum}},
  doi          = {10.1016/j.celrep.2021.109208},
  volume       = {35},
  year         = {2021},
}

@article{9073,
  abstract     = {The sensory and cognitive abilities of the mammalian neocortex are underpinned by intricate columnar and laminar circuits formed from an array of diverse neuronal populations. One approach to determining how interactions between these circuit components give rise to complex behavior is to investigate the rules by which cortical circuits are formed and acquire functionality during development. This review summarizes recent research on the development of the neocortex, from genetic determination in neural stem cells through to the dynamic role that specific neuronal populations play in the earliest circuits of neocortex, and how they contribute to emergent function and cognition. While many of these endeavors take advantage of model systems, consideration will also be given to advances in our understanding of activity in nascent human circuits. Such cross-species perspective is imperative when investigating the mechanisms underlying the dysfunction of early neocortical circuits in neurodevelopmental disorders, so that one can identify targets amenable to therapeutic intervention.},
  author       = {Hanganu-Opatz, Ileana L. and Butt, Simon J. B. and Hippenmeyer, Simon and De Marco García, Natalia V. and Cardin, Jessica A. and Voytek, Bradley and Muotri, Alysson R.},
  issn         = {1529-2401},
  journal      = {The Journal of Neuroscience},
  keywords     = {General Neuroscience},
  number       = {5},
  pages        = {813--822},
  publisher    = {Society for Neuroscience},
  title        = {{The logic of developing neocortical circuits in health and disease}},
  doi          = {10.1523/jneurosci.1655-20.2020},
  volume       = {41},
  year         = {2021},
}

@unpublished{9082,
  abstract     = {Acquired mutations are sufficiently frequent such that the genome of a single cell offers a record of its history of cell divisions. Among more common somatic genomic alterations are loss of heterozygosity (LOH). Large LOH events are potentially detectable in single cell RNA sequencing (scRNA-seq) datasets as tracts of monoallelic expression for constitutionally heterozygous single nucleotide variants (SNVs) located among contiguous genes. We identified runs of monoallelic expression, consistent with LOH, uniquely distributed throughout the genome in single cell brain cortex transcriptomes of F1 hybrids involving different inbred mouse strains. We then phylogenetically reconstructed single cell lineages and simultaneously identified cell types by corresponding gene expression patterns. Our results are consistent with progenitor cells giving rise to multiple cortical cell types through stereotyped expansion and distinct waves of neurogenesis. Compared to engineered recording systems, LOH events accumulate throughout the genome and across the lifetime of an organism, affording tremendous capacity for encoding lineage information and increasing resolution for later cell divisions. This approach can conceivably be computationally incorporated into scRNA-seq analysis and may be useful for organisms where genetic engineering is prohibitive, such as humans.},
  author       = {Anderson, Donovan J. and Pauler, Florian and McKenna, Aaron and Shendure, Jay and Hippenmeyer, Simon and Horwitz, Marshall S.},
  booktitle    = {bioRxiv},
  publisher    = {Cold Spring Harbor Laboratory},
  title        = {{Simultaneous identification of brain cell type and lineage via single cell RNA sequencing}},
  doi          = {10.1101/2020.12.31.425016},
  year         = {2021},
}

@article{9188,
  abstract     = {Genomic imprinting is an epigenetic mechanism that results in parental allele-specific expression of ~1% of all genes in mouse and human. Imprinted genes are key developmental regulators and play pivotal roles in many biological processes such as nutrient transfer from the mother to offspring and neuronal development. Imprinted genes are also involved in human disease, including neurodevelopmental disorders, and often occur in clusters that are regulated by a common imprint control region (ICR). In extra-embryonic tissues ICRs can act over large distances, with the largest surrounding Igf2r spanning over 10 million base-pairs. Besides classical imprinted expression that shows near exclusive maternal or paternal expression, widespread biased imprinted expression has been identified mainly in brain. In this review we discuss recent developments mapping cell type specific imprinted expression in extra-embryonic tissues and neocortex in the mouse. We highlight the advantages of using an inducible uniparental chromosome disomy (UPD) system to generate cells carrying either two maternal or two paternal copies of a specific chromosome to analyze the functional consequences of genomic imprinting. Mosaic Analysis with Double Markers (MADM) allows fluorescent labeling and concomitant induction of UPD sparsely in specific cell types, and thus to over-express or suppress all imprinted genes on that chromosome. To illustrate the utility of this technique, we explain how MADM-induced UPD revealed new insights about the function of the well-studied Cdkn1c imprinted gene, and how MADM-induced UPDs led to identification of highly cell type specific phenotypes related to perturbed imprinted expression in the mouse neocortex. Finally, we give an outlook on how MADM could be used to probe cell type specific imprinted expression in other tissues in mouse, particularly in extra-embryonic tissues.},
  author       = {Pauler, Florian and Hudson, Quanah and Laukoter, Susanne and Hippenmeyer, Simon},
  issn         = {0197-0186},
  journal      = {Neurochemistry International},
  keywords     = {Cell Biology, Cellular and Molecular Neuroscience},
  number       = {5},
  publisher    = {Elsevier},
  title        = {{Inducible uniparental chromosome disomy to probe genomic imprinting at single-cell level in brain and beyond}},
  doi          = {10.1016/j.neuint.2021.104986},
  volume       = {145},
  year         = {2021},
}

@article{9603,
  abstract     = {Mosaic analysis with double markers (MADM) offers one approach to visualize and concomitantly manipulate genetically defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage, single-cell morphology and physiology, genomic imprinting phenotypes, and dissection of cell-autonomous gene functions in vivo in health and disease. Yet, MADM can only be applied to <25% of all mouse genes on select chromosomes to date. To overcome this limitation, we generate transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validate their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond a proof of principle, we apply our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We find striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.},
  author       = {Contreras, Ximena and Amberg, Nicole and Davaatseren, Amarbayasgalan and Hansen, Andi H and Sonntag, Johanna and Andersen, Lill and Bernthaler, Tina and Streicher, Carmen and Heger, Anna-Magdalena and Johnson, Randy L. and Schwarz, Lindsay A. and Luo, Liqun and Rülicke, Thomas and Hippenmeyer, Simon},
  issn         = {22111247},
  journal      = {Cell Reports},
  number       = {12},
  publisher    = {Cell Press},
  title        = {{A genome-wide library of MADM mice for single-cell genetic mosaic analysis}},
  doi          = {10.1016/j.celrep.2021.109274},
  volume       = {35},
  year         = {2021},
}

@article{10321,
  abstract     = {Mosaic analysis with double markers (MADM) technology enables the generation of genetic mosaic tissue in mice. MADM enables concomitant fluorescent cell labeling and introduction of a mutation of a gene of interest with single-cell resolution. This protocol highlights major steps for the generation of genetic mosaic tissue and the isolation and processing of respective tissues for downstream histological analysis. For complete details on the use and execution of this protocol, please refer to Contreras et al. (2021).},
  author       = {Amberg, Nicole and Hippenmeyer, Simon},
  issn         = {2666-1667},
  journal      = {STAR Protocols},
  number       = {4},
  publisher    = {Cell Press},
  title        = {{Genetic mosaic dissection of candidate genes in mice using mosaic analysis with double markers}},
  doi          = {10.1016/j.xpro.2021.100939},
  volume       = {2},
  year         = {2021},
}

@article{9793,
  abstract     = {Astrocytes extensively infiltrate the neuropil to regulate critical aspects of synaptic development and function. This process is regulated by transcellular interactions between astrocytes and neurons via cell adhesion molecules. How astrocytes coordinate developmental processes among one another to parse out the synaptic neuropil and form non-overlapping territories is unknown. Here we identify a molecular mechanism regulating astrocyte-astrocyte interactions during development to coordinate astrocyte morphogenesis and gap junction coupling. We show that hepaCAM, a disease-linked, astrocyte-enriched cell adhesion molecule, regulates astrocyte competition for territory and morphological complexity in the developing mouse cortex. Furthermore, conditional deletion of Hepacam from developing astrocytes significantly impairs gap junction coupling between astrocytes and disrupts the balance between synaptic excitation and inhibition. Mutations in HEPACAM cause megalencephalic leukoencephalopathy with subcortical cysts in humans. Therefore, our findings suggest that disruption of astrocyte self-organization mechanisms could be an underlying cause of neural pathology.},
  author       = {Baldwin, Katherine T. and Tan, Christabel X. and Strader, Samuel T. and Jiang, Changyu and Savage, Justin T. and Elorza-Vidal, Xabier and Contreras, Ximena and Rülicke, Thomas and Hippenmeyer, Simon and Estévez, Raúl and Ji, Ru-Rong and Eroglu, Cagla},
  issn         = {1097-4199},
  journal      = {Neuron},
  number       = {15},
  pages        = {2427--2442.e10},
  publisher    = {Elsevier},
  title        = {{HepaCAM controls astrocyte self-organization and coupling}},
  doi          = {10.1016/j.neuron.2021.05.025},
  volume       = {109},
  year         = {2021},
}

@article{7814,
  abstract     = {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.},
  author       = {Beattie, Robert J and Hippenmeyer, Simon and Pauler, Florian},
  issn         = {2504-284X},
  journal      = {Frontiers in Education},
  publisher    = {Frontiers Media},
  title        = {{SCOPES: Sparking curiosity through Open-Source platforms in education and science}},
  doi          = {10.3389/feduc.2020.00048},
  volume       = {5},
  year         = {2020},
}

@article{7815,
  abstract     = {Beginning from a limited pool of progenitors, the mammalian cerebral cortex forms highly organized functional neural circuits. However, the underlying cellular and molecular mechanisms regulating lineage transitions of neural stem cells (NSCs) and eventual production of neurons and glia in the developing neuroepithelium remains unclear. Methods to trace NSC division patterns and map the lineage of clonally related cells have advanced dramatically. However, many contemporary lineage tracing techniques suffer from the lack of cellular resolution of progeny cell fate, which is essential for deciphering progenitor cell division patterns. Presented is a protocol using mosaic analysis with double markers (MADM) to perform in vivo clonal analysis. MADM concomitantly manipulates individual progenitor cells and visualizes precise division patterns and lineage progression at unprecedented single cell resolution. MADM-based interchromosomal recombination events during the G2-X phase of mitosis, together with temporally inducible CreERT2, provide exact information on the birth dates of clones and their division patterns. Thus, MADM lineage tracing provides unprecedented qualitative and quantitative optical readouts of the proliferation mode of stem cell progenitors at the single cell level. MADM also allows for examination of the mechanisms and functional requirements of candidate genes in NSC lineage progression. This method is unique in that comparative analysis of control and mutant subclones can be performed in the same tissue environment in vivo. Here, the protocol is described in detail, and experimental paradigms to employ MADM for clonal analysis and lineage tracing in the developing cerebral cortex are demonstrated. Importantly, this protocol can be adapted to perform MADM clonal analysis in any murine stem cell niche, as long as the CreERT2 driver is present.},
  author       = {Beattie, Robert J and Streicher, Carmen and Amberg, Nicole and Cheung, Giselle T and Contreras, Ximena and Hansen, Andi H and Hippenmeyer, Simon},
  issn         = {1940-087X},
  journal      = {Journal of Visual Experiments},
  number       = {159},
  publisher    = {MyJove Corporation},
  title        = {{Lineage tracing and clonal analysis in developing cerebral cortex using mosaic analysis with double markers (MADM)}},
  doi          = {10.3791/61147},
  year         = {2020},
}

@phdthesis{7902,
  abstract     = {Mosaic genetic analysis has been widely used in different model organisms such as the fruit fly to study gene-function in a cell-autonomous or tissue-specific fashion. More recently, and less easily conducted, mosaic genetic analysis in mice has also been enabled with the ambition to shed light on human gene function and disease. These genetic tools are of particular interest, but not restricted to, the study of the brain. Notably, the MADM technology offers a genetic approach in mice to visualize and concomitantly manipulate small subsets of genetically defined cells at a clonal level and single cell resolution. MADM-based analysis has already advanced the study of genetic mechanisms regulating brain development and is expected that further MADM-based analysis of genetic alterations will continue to reveal important insights on the fundamental principles of development and disease to potentially assist in the development of new therapies or treatments.
In summary, this work completed and characterized the necessary genome-wide genetic tools to perform MADM-based analysis at single cell level of the vast majority of mouse genes in virtually any cell type and provided a protocol to perform lineage tracing using the novel MADM resource. Importantly, this work also explored and revealed novel aspects of biologically relevant events in an in vivo context, such as the chromosome-specific bias of chromatid sister segregation pattern, the generation of cell-type diversity in the cerebral cortex and in the cerebellum and finally, the relevance of the interplay between the cell-autonomous gene function and cell-non-autonomous (community) effects in radial glial progenitor lineage progression.
This work provides a foundation and opens the door to further elucidating the molecular mechanisms underlying neuronal diversity and astrocyte generation.},
  author       = {Contreras, Ximena},
  issn         = {2663-337X},
  pages        = {214},
  publisher    = {Institute of Science and Technology Austria},
  title        = {{Genetic dissection of neural development in health and disease at single cell resolution}},
  doi          = {10.15479/AT:ISTA:7902},
  year         = {2020},
}

@article{8162,
  abstract     = {In mammalian genomes, a subset of genes is regulated by genomic imprinting, resulting in silencing of one parental allele. Imprinting is essential for cerebral cortex development, but prevalence and functional impact in individual cells is unclear. Here, we determined allelic expression in cortical cell types and established a quantitative platform to interrogate imprinting in single cells. We created cells with uniparental chromosome disomy (UPD) containing two copies of either the maternal or the paternal chromosome; hence, imprinted genes will be 2-fold overexpressed or not expressed. By genetic labeling of UPD, we determined cellular phenotypes and transcriptional responses to deregulated imprinted gene expression at unprecedented single-cell resolution. We discovered an unexpected degree of cell-type specificity and a novel function of imprinting in the regulation of cortical astrocyte survival. More generally, our results suggest functional relevance of imprinted gene expression in glial astrocyte lineage and thus for generating cortical cell-type diversity.},
  author       = {Laukoter, Susanne and Pauler, Florian and Beattie, Robert J and Amberg, Nicole and Hansen, Andi H and Streicher, Carmen and Penz, Thomas and Bock, Christoph and Hippenmeyer, Simon},
  issn         = {0896-6273},
  journal      = {Neuron},
  number       = {6},
  pages        = {1160--1179.e9},
  publisher    = {Elsevier},
  title        = {{Cell-type specificity of genomic imprinting in cerebral cortex}},
  doi          = {10.1016/j.neuron.2020.06.031},
  volume       = {107},
  year         = {2020},
}

@article{8592,
  abstract     = {Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells‐of‐origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin‐like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new‐generation brain‐penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.},
  author       = {Tian, Anhao and Kang, Bo and Li, Baizhou and Qiu, Biying and Jiang, Wenhong and Shao, Fangjie and Gao, Qingqing and Liu, Rui and Cai, Chengwei and Jing, Rui and Wang, Wei and Chen, Pengxiang and Liang, Qinghui and Bao, Lili and Man, Jianghong and Wang, Yan and Shi, Yu and Li, Jin and Yang, Minmin and Wang, Lisha and Zhang, Jianmin and Hippenmeyer, Simon and Zhu, Junming and Bian, Xiuwu and Wang, Ying‐Jie and Liu, Chong},
  issn         = {2198-3844},
  journal      = {Advanced Science},
  keywords     = {General Engineering, General Physics and Astronomy, General Materials Science, Medicine (miscellaneous), General Chemical Engineering, Biochemistry, Genetics and Molecular Biology (miscellaneous)},
  number       = {21},
  publisher    = {Wiley},
  title        = {{Oncogenic state and cell identity combinatorially dictate the susceptibility of cells within glioma development hierarchy to IGF1R targeting}},
  doi          = {10.1002/advs.202001724},
  volume       = {7},
  year         = {2020},
}

@unpublished{8616,
  abstract     = {The brain vasculature supplies neurons with glucose and oxygen, but little is known about how vascular plasticity contributes to brain function. Using longitudinal <jats:italic>in vivo</jats:italic> 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.},
  author       = {Gao, Xiaofei and Li, Jun-Liszt and Chen, Xingjun and Ci, Bo and Chen, Fei and Lu, Nannan and Shen, Bo and Zheng, Lijun and Jia, Jie-Min and Yi, Yating and Zhang, Shiwen and Shi, Ying-Chao and Shi, Kaibin and Propson, Nicholas E and Huang, Yubin and Poinsatte, Katherine and Zhang, Zhaohuan and Yue, Yuanlei and Bosco, Dale B and Lu, Ying-mei and Yang, Shi-bing and Adams, Ralf H. and Lindner, Volkhard and Huang, Fen and Wu, Long-Jun and Zheng, Hui and Han, Feng and Hippenmeyer, Simon and Stowe, Ann M. and Peng, Bo and Margeta, Marta and Wang, Xiaoqun and Liu, Qiang and Körbelin, Jakob and Trepel, Martin and Lu, Hui and Zhou, Bo O. and Zhao, Hu and Su, Wenzhi and Bachoo, Robert M. and Ge, Woo-ping},
  booktitle    = {bioRxiv},
  publisher    = {Cold Spring Harbor Laboratory},
  title        = {{Reduction of neuronal activity mediated by blood-vessel regression in the brain}},
  doi          = {10.1101/2020.09.15.262782},
  year         = {2020},
}

@article{8949,
  abstract     = {<jats:p>Development of the nervous system undergoes important transitions, including one from neurogenesis to gliogenesis which occurs late during embryonic gestation. Here we report on clonal analysis of gliogenesis in mice using Mosaic Analysis with Double Markers (MADM) with quantitative and computational methods. Results reveal that developmental gliogenesis in the cerebral cortex occurs in a fraction of earlier neurogenic clones, accelerating around E16.5, and giving rise to both astrocytes and oligodendrocytes. Moreover, MADM-based genetic deletion of the epidermal growth factor receptor (Egfr) in gliogenic clones revealed that Egfr is cell autonomously required for gliogenesis in the mouse dorsolateral cortices. A broad range in the proliferation capacity, symmetry of clones, and competitive advantage of MADM cells was evident in clones that contained one cellular lineage with double dosage of Egfr relative to their environment, while their sibling Egfr-null cells failed to generate glia. Remarkably, the total numbers of glia in MADM clones balance out regardless of significant alterations in clonal symmetries. The variability in glial clones shows stochastic patterns that we define mathematically, which are different from the deterministic patterns in neuronal clones. This study sets a foundation for studying the biological significance of stochastic and deterministic clonal principles underlying tissue development, and identifying mechanisms that differentiate between neurogenesis and gliogenesis.</jats:p>},
  author       = {Zhang, Xuying and Mennicke, Christine V. and Xiao, Guanxi and Beattie, Robert J and Haider, Mansoor and Hippenmeyer, Simon and Ghashghaei, H. Troy},
  issn         = {2073-4409},
  journal      = {Cells},
  number       = {12},
  publisher    = {MDPI},
  title        = {{Clonal analysis of gliogenesis in the cerebral cortex reveals stochastic expansion of glia and cell autonomous responses to Egfr dosage}},
  doi          = {10.3390/cells9122662},
  volume       = {9},
  year         = {2020},
}