@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{27, abstract = {The cerebral cortex is composed of a large variety of distinct cell-types including projection neurons, interneurons and glial cells which emerge from distinct neural stem cell (NSC) lineages. The vast majority of cortical projection neurons and certain classes of glial cells are generated by radial glial progenitor cells (RGPs) in a highly orchestrated manner. Recent studies employing single cell analysis and clonal lineage tracing suggest that NSC and RGP lineage progression are regulated in a profound deterministic manner. In this review we focus on recent advances based mainly on correlative phenotypic data emerging from functional genetic studies in mice. We establish hypotheses to test in future research and outline a conceptual framework how epigenetic cues modulate the generation of cell-type diversity during cortical development. This article is protected by copyright. All rights reserved.}, author = {Amberg, Nicole and Laukoter, Susanne and Hippenmeyer, Simon}, journal = {Journal of Neurochemistry}, number = {1}, pages = {12--26}, publisher = {Wiley}, title = {{Epigenetic cues modulating the generation of cell type diversity in the cerebral cortex}}, doi = {10.1111/jnc.14601}, volume = {149}, year = {2019}, } @article{621, abstract = {The mammalian cerebral cortex is responsible for higher cognitive functions such as perception, consciousness, and acquiring and processing information. The neocortex is organized into six distinct laminae, each composed of a rich diversity of cell types which assemble into highly complex cortical circuits. Radial glia progenitors (RGPs) are responsible for producing all neocortical neurons and certain glia lineages. Here, we discuss recent discoveries emerging from clonal lineage analysis at the single RGP cell level that provide us with an inaugural quantitative framework of RGP lineage progression. We further discuss the importance of the relative contribution of intrinsic gene functions and non-cell-autonomous or community effects in regulating RGP proliferation behavior and lineage progression.}, author = {Beattie, Robert J and Hippenmeyer, Simon}, issn = {00145793}, journal = {FEBS letters}, number = {24}, pages = {3993 -- 4008}, publisher = {Wiley-Blackwell}, title = {{Mechanisms of radial glia progenitor cell lineage progression}}, doi = {10.1002/1873-3468.12906}, volume = {591}, year = {2017}, } @article{944, abstract = {The concerted production of neurons and glia by neural stem cells (NSCs) is essential for neural circuit assembly. In the developing cerebral cortex, radial glia progenitors (RGPs) generate nearly all neocortical neurons and certain glia lineages. RGP proliferation behavior shows a high degree of non-stochasticity, thus a deterministic characteristic of neuron and glia production. However, the cellular and molecular mechanisms controlling RGP behavior and proliferation dynamics in neurogenesis and glia generation remain unknown. By using mosaic analysis with double markers (MADM)-based genetic paradigms enabling the sparse and global knockout with unprecedented single-cell resolution, we identified Lgl1 as a critical regulatory component. We uncover Lgl1-dependent tissue-wide community effects required for embryonic cortical neurogenesis and novel cell-autonomous Lgl1 functions controlling RGP-mediated glia genesis and postnatal NSC behavior. These results suggest that NSC-mediated neuron and glia production is tightly regulated through the concerted interplay of sequential Lgl1-dependent global and cell intrinsic mechanisms.}, author = {Beattie, Robert J and Postiglione, Maria P and Burnett, Laura and Laukoter, Susanne and Streicher, Carmen and Pauler, Florian and Xiao, Guanxi and Klezovitch, Olga and Vasioukhin, Valeri and Ghashghaei, Troy and Hippenmeyer, Simon}, issn = {08966273}, journal = {Neuron}, number = {3}, pages = {517 -- 533.e3}, publisher = {Cell Press}, title = {{Mosaic analysis with double markers reveals distinct sequential functions of Lgl1 in neural stem cells}}, doi = {10.1016/j.neuron.2017.04.012}, volume = {94}, year = {2017}, } @article{960, abstract = {The human cerebral cortex is the seat of our cognitive abilities and composed of an extraordinary number of neurons, organized in six distinct layers. The establishment of specific morphological and physiological features in individual neurons needs to be regulated with high precision. Impairments in the sequential developmental programs instructing corticogenesis lead to alterations in the cortical cytoarchitecture which is thought to represent the major underlying cause for several neurological disorders including neurodevelopmental and psychiatric diseases. In this review we discuss the role of cell polarity at sequential stages during cortex development. We first provide an overview of morphological cell polarity features in cortical neural stem cells and newly-born postmitotic neurons. We then synthesize a conceptual molecular and biochemical framework how cell polarity is established at the cellular level through a break in symmetry in nascent cortical projection neurons. Lastly we provide a perspective how the molecular mechanisms applying to single cells could be probed and integrated in an in vivo and tissue-wide context.}, author = {Hansen, Andi H and Düllberg, Christian F and Mieck, Christine and Loose, Martin and Hippenmeyer, Simon}, issn = {16625102}, journal = {Frontiers in Cellular Neuroscience}, publisher = {Frontiers Research Foundation}, title = {{Cell polarity in cerebral cortex development - cellular architecture shaped by biochemical networks}}, doi = {10.3389/fncel.2017.00176}, volume = {11}, year = {2017}, } @article{1181, abstract = {This review accompanies a 2016 SFN mini-symposium presenting examples of current studies that address a central question: How do neural stem cells (NSCs) divide in different ways to produce heterogeneous daughter types at the right time and in proper numbers to build a cerebral cortex with the appropriate size and structure? We will focus on four aspects of corticogenesis: cytokinesis events that follow apical mitoses of NSCs; coordinating abscission with delamination from the apical membrane; timing of neurogenesis and its indirect regulation through emergence of intermediate progenitors; and capacity of single NSCs to generate the correct number and laminar fate of cortical neurons. Defects in these mechanisms can cause microcephaly and other brain malformations, and understanding them is critical to designing diagnostic tools and preventive and corrective therapies.}, author = {Dwyer, Noelle and Chen, Bin and Chou, Shen and Hippenmeyer, Simon and Nguyen, Laurent and Ghashghaei, Troy}, journal = {Journal of Neuroscience}, number = {45}, pages = {11394 -- 11401}, publisher = {Society for Neuroscience}, title = {{Neural stem cells to cerebral cortex: Emerging mechanisms regulating progenitor behavior and productivity}}, doi = {10.1523/JNEUROSCI.2359-16.2016}, volume = {36}, year = {2016}, } @article{2022, abstract = {Radial glial progenitors (RGPs) are responsible for producing nearly all neocortical neurons. To gain insight into the patterns of RGP division and neuron production, we quantitatively analyzed excitatory neuron genesis in the mouse neocortex using Mosaic Analysis with Double Markers, which provides single-cell resolution of progenitor division patterns and potential in vivo. We found that RGPs progress through a coherent program in which their proliferative potential diminishes in a predictable manner. Upon entry into the neurogenic phase, individual RGPs produce ∼8–9 neurons distributed in both deep and superficial layers, indicating a unitary output in neuronal production. Removal of OTX1, a transcription factor transiently expressed in RGPs, results in both deep- and superficial-layer neuron loss and a reduction in neuronal unit size. Moreover, ∼1/6 of neurogenic RGPs proceed to produce glia. These results suggest that progenitor behavior and histogenesis in the mammalian neocortex conform to a remarkably orderly and deterministic program.}, author = {Gao, Peng and Postiglione, Maria P and Krieger, Teresa and Hernandez, Luisirene and Wang, Chao and Han, Zhi and Streicher, Carmen and Papusheva, Ekaterina and Insolera, Ryan and Chugh, Kritika and Kodish, Oren and Huang, Kun and Simons, Benjamin and Luo, Liqun and Hippenmeyer, Simon and Shi, Song}, journal = {Cell}, number = {4}, pages = {775 -- 788}, publisher = {Cell Press}, title = {{Deterministic progenitor behavior and unitary production of neurons in the neocortex}}, doi = {10.1016/j.cell.2014.10.027}, volume = {159}, year = {2014}, }