DOT1L deletion impairs the development of cortical parvalbumin-expressing interneurons

The cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, interneuron precursors migrate during embryonic development over some distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is necessary for proper cortical plate development and layer distribution of glutamatergic neurons, however, its specific role on cortical interneuron development has not yet been explored. Here, we demonstrate that DOT1L affects interneuron development in a cell-autonomous manner. Deletion of Dot1l in MGE-derived interneuron precursor cells results in an overall reduction and altered distribution of GABAergic interneurons in the cortical plate at postnatal day (P) 0. Furthermore, we observed an altered proportion of GABAergic interneurons in the cortex and striatum at P21 with a significant decrease in Parvalbumin (PVALB)-expressing interneurons. Altogether, our results indicate that reduced numbers of cortical interneurons upon DOT1L deletion results from altered post-mitotic differentiation/maturation.

[1]  N. Kessaris,et al.  MTG8 interacts with LHX6 to specify cortical interneuron subtype identity , 2022, Nature Communications.

[2]  Rachel C. Bandler,et al.  Single-cell delineation of lineage and genetic identity in the mouse brain , 2021, Nature.

[3]  E. Marsh,et al.  Islet1 Precursors Contribute to Mature Interneuron Subtypes in Mouse Neocortex. , 2021, Cerebral cortex.

[4]  Xiaochen Bo,et al.  clusterProfiler 4.0: A universal enrichment tool for interpreting omics data , 2021, Innovation.

[5]  H. Nam,et al.  The Role of Parvalbumin Interneurons in Neurotransmitter Balance and Neurological Disease , 2021, Frontiers in Psychiatry.

[6]  B. Garcia,et al.  Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons , 2021, Nature Neuroscience.

[7]  F. Ferrari,et al.  DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility , 2020, Nature Communications.

[8]  C. Konradi,et al.  Parvalbumin interneuron vulnerability and brain disorders , 2020, Neuropsychopharmacology.

[9]  Daniel J. Blankenberg,et al.  The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2020 update , 2020, Nucleic acids research.

[10]  D. Jabaudon,et al.  PlexinA4-Semaphorin3A mediated crosstalk between main cortical interneuron classes is required for superficial interneurons lamination , 2020, bioRxiv.

[11]  E. Sibille,et al.  Altered GABA-mediated information processing and cognitive dysfunctions in depression and other brain disorders , 2020, Molecular Psychiatry.

[12]  F. Ferrari,et al.  Differentiation and localization of interneurons in the developing spinal cord depends on DOT1L expression , 2020, Molecular Brain.

[13]  K. Harris,et al.  Hippocampal CA1 Somatostatin Interneurons Originate in the Embryonic MGE/POA , 2019, Stem cell reports.

[14]  Jason C. Wester,et al.  Neocortical Projection Neurons Instruct Inhibitory Interneuron Circuit Development in a Lineage-Dependent Manner , 2019, Neuron.

[15]  R. Backofen,et al.  DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex , 2018, Nucleic acids research.

[16]  Fabian Kilpert,et al.  Differential Methylation of H3K79 Reveals DOT1L Target Genes and Function in the Cerebellum In Vivo , 2018, Molecular Neurobiology.

[17]  Mingfeng Li,et al.  Early emergence of cortical interneuron diversity in the mouse embryo , 2018, Science.

[18]  Christoph Hafemeister,et al.  Developmental diversification of cortical inhibitory interneurons , 2017, Nature.

[19]  D. Lewis,et al.  Distinct Physiological Maturation of Parvalbumin-Positive Neuron Subtypes in Mouse Prefrontal Cortex , 2017, The Journal of Neuroscience.

[20]  S. Durinck,et al.  Single-cell RNA sequencing identifies distinct mouse medial ganglionic eminence cell types , 2017, Scientific Reports.

[21]  O. Marín,et al.  Neuregulin 3 Mediates Cortical Plate Invasion and Laminar Allocation of GABAergic Interneurons , 2017, Cell reports.

[22]  A. Visel,et al.  Transcriptional Networks Controlled by NKX2-1 in the Development of Forebrain GABAergic Neurons , 2016, Neuron.

[23]  R. Tremblay,et al.  GABAergic Interneurons in the Neocortex: From Cellular Properties to Circuits , 2016, Neuron.

[24]  N. Hellbach,et al.  DOT1L Activity Promotes Proliferation and Protects Cortical Neural Stem Cells from Activation of ATF4‐DDIT3‐Mediated ER Stress In Vitro , 2016, Stem cells.

[25]  Gord Fishell,et al.  Apical versus Basal Neurogenesis Directs Cortical Interneuron Subclass Fate. , 2015, Cell reports.

[26]  R. Romcy-Pereira,et al.  Interplay of environmental signals and progenitor diversity on fate specification of cortical GABAergic neurons , 2015, Front. Cell. Neurosci..

[27]  W. Huber,et al.  Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2 , 2014, Genome Biology.

[28]  J. Partanen,et al.  Mechanisms regulating GABAergic neuron development , 2014, Cellular and Molecular Life Sciences.

[29]  K. Nakashima,et al.  Epigenetic regulation of neural stem cell fate during corticogenesis , 2013, International Journal of Developmental Neuroscience.

[30]  J. Britto,et al.  Neurons on the Move: Migration and Lamination of Cortical Interneurons , 2012, Neurosignals.

[31]  S. Anderson,et al.  Spatial and temporal bias in the mitotic origins of somatostatin- and parvalbumin-expressing interneuron subgroups and the chandelier subtype in the medial ganglionic eminence. , 2012, Cerebral cortex.

[32]  Arno C. Schmitt,et al.  Inhibitory interneurons in a cortical column form hot zones of inhibition in layers 2 and 5A , 2011, Proceedings of the National Academy of Sciences.

[33]  G. Miyoshi,et al.  GABAergic interneuron lineages selectively sort into specific cortical layers during early postnatal development. , 2011, Cerebral cortex.

[34]  O. Marín,et al.  Cxcr7 Controls Neuronal Migration by Regulating Chemokine Responsiveness , 2011, Neuron.

[35]  K. Nakashima,et al.  Epigenetic regulation in neural stem cell differentiation , 2010, Development, growth & differentiation.

[36]  S. Kügler,et al.  AF9/MLLT3 interferes with TBR1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex , 2010, International Journal of Developmental Neuroscience.

[37]  O. Marín,et al.  The Embryonic Preoptic Area Is a Novel Source of Cortical GABAergic Interneurons , 2009, The Journal of Neuroscience.

[38]  S. Anderson,et al.  Postmitotic Nkx2-1 Controls the Migration of Telencephalic Interneurons by Direct Repression of Guidance Receptors , 2008, Neuron.

[39]  O. Marín,et al.  Chemokine Signaling Controls Intracortical Migration and Final Distribution of GABAergic Interneurons , 2008, The Journal of Neuroscience.

[40]  S. Anderson,et al.  A spatial bias for the origins of interneuron subgroups within the medial ganglionic eminence. , 2008, Developmental biology.

[41]  S. Anderson,et al.  Fate mapping Nkx2.1‐lineage cells in the mouse telencephalon , 2008, The Journal of comparative neurology.

[42]  O. Marín,et al.  Delineation of Multiple Subpallial Progenitor Domains by the Combinatorial Expression of Transcriptional Codes , 2007, The Journal of Neuroscience.

[43]  Y. Yanagawa,et al.  Lhx6 Activity Is Required for the Normal Migration and Specification of Cortical Interneuron Subtypes , 2007, The Journal of Neuroscience.

[44]  S. Anderson,et al.  The origin and specification of cortical interneurons , 2006, Nature Reviews Neuroscience.

[45]  J. C. Belmonte,et al.  Sp8 and Sp9, two closely related buttonhead-like transcription factors, regulate Fgf8 expression and limb outgrowth in vertebrate embryos , 2004, Development.

[46]  O. Marín,et al.  A long, remarkable journey: Tangential migration in the telencephalon , 2001, Nature Reviews Neuroscience.

[47]  Shankar Srinivas,et al.  Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus , 2001, BMC Developmental Biology.

[48]  S. Mcconnell,et al.  Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. , 2000, Developmental biology.

[49]  A. Lavdas,et al.  The Medial Ganglionic Eminence Gives Rise to a Population of Early Neurons in the Developing Cerebral Cortex , 1999, The Journal of Neuroscience.

[50]  E. Lai,et al.  Dual role of brain factor-1 in regulating growth and patterning of the cerebral hemispheres. , 1999, Cerebral cortex.

[51]  P. Rakic.  Radial versus tangential migration of neuronal clones in the developing cerebral cortex. , 1995, Proceedings of the National Academy of Sciences of the United States of America.