Resources for "A Multimodal Cell Census and Atlas of the Mammalian Primary Motor Cortex", 2021
We report the generation of a multimodal cell census and atlas of the mammalian primary motor cortex (MOp or M1) as the initial product of the BRAIN Initiative Cell Census Network (BICCN). This was achieved by coordinated large-scale analyses of single-cell transcriptomes, chromatin accessibility, DNA methylomes, spatially resolved single-cell transcriptomes, morphological and electrophysiological properties, and cellular resolution input-output mapping, integrated through cross-modal computational analysis. The study reveals a unified molecular genetic landscape of cortical cell types that congruently integrates their transcriptome, open chromatin and DNA methylation maps. Second, cross-species analysis achieves a unified taxonomy of transcriptomic types and their hierarchical organization that are conserved from mouse to marmoset and human. Third, cross-modal analysis provides compelling evidence for the epigenomic, transcriptomic, and gene regulatory basis of neuronal phenotypes such as their physiological and anatomical properties, demonstrating the biological validity and genomic underpinning of neuron types and subtypes. Fourth, in situ single-cell transcriptomics provides a spatially-resolved cell type atlas of the motor cortex. Fifth, integrated transcriptomic, epigenomic and anatomical analyses reveal the correspondence between neural circuits and transcriptomic cell types. We further present an extensive genetic toolset for targeting and fate mapping glutamatergic projection neuron types toward linking their developmental trajectory to their circuit function. This page provides a guide to access accessing data and tools associated with this work
A series of companion studies supported the findings in this manuscript.
- An integrated transcriptomic and epigenomic atlas of mouse primary motor cortex cell types, Yao et al., 2020
- Evolution of cellular diversity in primary motor cortex of human, marmoset monkey, and mouse, Bakken et al., 2020
- Molecular, spatial and projection diversity of neurons in primary motor cortex revealed by in situ single-cell transcriptomics, Zhang et al, 2020
- Phenotypic variation of transcriptomic cell types in mouse motor cortex, Scala et al, 2020
- Cellular Anatomy of the Mouse Primary Motor Cortex, Munoz-Casteneda, 2020
- Genetic dissection of the glutamatergic neuron system in cerebral cortex, Matho et al,2020
- DNA Methylation Atlas of the Mouse Brain at Single-Cell Resolution, Liu et al., 2020
- Epigenomic Diversity of Cortical Projection Neurons in the Mouse Brain, Zhang et al., 2020
- An atlas of gene regulatory elements in Adult Mouse Cerebrum, Li et al, 2020
- Human cortical expansion involves diversification and specialization of supragranular intratelencephalic-projecting neurons, Berg et al,2020
- Brain-wide single neuron reconstruction reveals morphological diversity in molecularly defined striatal, thalamic, cortical and claustral neuron types, Peng et al,2020
Data and supporting code related to analyses in figures.
- Figure 1: Summary of experimental and computational approaches taken and as well as community resources generated by BICCN.
- Figure 2: MOp consensus cell type taxonomy.
- Figure 3: In situ cell-type identification, spatial mapping and projection mapping of individual cells in the MOp by MERFISH
- Figure 4: Correspondence between transcriptomic and morpho-electrical properties of mouse MOp neurons by Patch-seq, and cross-species comparison of L5 ET neurons.
- Figure 5: Epi-Retro-Seq links molecular cell types with distal projection targets.
- Figure 6: Genetic tools for targeting cortical glutamatergic projection neuron types.
- Figure 7: Global wiring diagram and anatomical characterization of MOp-ul neuron types.
- Figure 8: Existence of L4 excitatory neurons in MOp.
- Figure 9: Two distinct L5 ET projection neuron types in MOp.
- Figure 10: An integrated multimodal census and atlas of cell types in the primary motor cortex of mouse, marmoset and human.
Temporarily, links to BIL-hosted datasets will direct one to the raw data directories at BIL. As BIL creates landing pages for these datasets, these links will be replaced with links to the landing pages, which will include a description of the dataset, the generating lab, contact info, and downloading info.
Figure 1: Summary of experimental and computational approaches taken and as well as community resources generated by BICCN
All primary data is accessible through the Brain Cell Data Center and data archives.
- Brain Cell Data Center (BCDC), Overall BICCN organization and data, www.biccn.org
BRAIN Initiative Data Archives
-
Neuroscience Multi-omic Data Archive (NeMO), RRID:SCR_016152
-
Brain Image Library (BIL), RRID:SCR_017272
-
Distributed Archives for Neurophysiology Data Integration (DANDI), RRID:SCR_017571
Analysis platform for BICCN -omics datasets
- NeMO Analytics
The following papers are referenced techniques other than those in the companion papers.
- Shared and distinct transcriptomic cell types across neocortical areas, Tasic et al., 2018
- Conserved cell types with divergent features in human versus mouse cortex, Hodge et al., 2019
- Innovations present in the primate interneuron repertoire, Krienen et al., 2020
- A transcriptomic atlas of the mouse cerebellum reveals regional specializations and novel cell types, Kozareva et al., 2020
- A taxonomy of transcriptomic cell types across the isocortex and hippocampal formation, Yao et al., 2020
- Robust single-cell DNA methylome profiling with snmC-seq2, Luo et al., 2018
- Spatiotemporal DNA methylome dynamics of the developing mouse fetus, He et al., 2018
- RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells, Chen et al., 2015
- Molecular, spatial, and functional single-cell profiling of the hypothalamic preoptic region, Moffitt et al., 2019
- Comprehensive integration of single cell data, Stuart et al., 2019
- Single-Cell Multi-omic Integration Compares and Contrasts Features of Brain Cell Identity, Welch et al., 2019
- Characterizing the replicability of cell types defined by single cell RNA-sequencing data using MetaNeighbor. Crow et al., 2018
- Electrophysiological, transcriptomic and morphologic profiling of single neurons using Patch-seq, Cadwell et al., 2016
- Multimodal profiling of single-cell morphology, electrophysiology, and gene expression using Patch-seq, Cadwell et al., 2017
- High-throughput dual-colour precision imaging for brain-wide connectome with cytoarchitectonic landmarks at the cellular level, Gong et al., 2016
- Reconstruction of 1,000 Projection Neurons Reveals New Cell Types and Organization of Long-Range Connectivity in the Mouse Brain, Winnubst et al. 2019
- An open repository for single-cell reconstructions of the brain forest, Akram et al, 2018
- Neural networks of the mouse cortex, Zingg et al., 2014
- AAV-Mediated Anterograde Transsynaptic Tagging: Mapping Corticocollicular Input-Defined Neural Pathways for Defense Behaviors, Zingg et al., 2017
| Resource | Description | Link | RRID |
|---|---|---|---|
| NeMO Analytics | Companion resources | NeMO | RRID:SCR_018164 |
| CATlas | Atlas of Cis-elements gene regulatory elements | CATlas | RRID:SCR_018690 |
| LIGER | Integrating multiple single cell datasets | LIGER | RRID:SCR_018100 |
| Neuromorpho.org | Inventory of digital reconstructed neurons | Neuromorpho | RRID:SCR_002145 |
| MetaNeighbor | Characterizing cell type replicability | MetaNeighbor | RRID:SCR_016727 |
| Patch-Seq | Companion resources | Mini-atlas PatchSeq | RRID:SCR_021115 |
| Allen CCF | Allen Mouse Brain Common Coordinate Framework | Atlas viewer | RRID:SCR_020999 |
| MORF Reporter | Reporter mouse resource page | MORF | RRID:SCR_021125 |
| Individual Mice from MORF | RRID:IMSR_JAX:035403, RRID:IMSR_JAX:035400, RRID:IMSR_JAX:035404 | ||
| CCN | Common Cell Type Nomenclature | CCN | RRID:SCR_021124 |
Note, individual tools created by or used by the BICCN consortium are accessible via the resource registry.
| Panel | Description of data collection | BICCN Project Summary Page | Repository Link |
|---|---|---|---|
| 2a | NEMO Publication Release Bundle for MOp MiniAtlas | NEMO | |
| 2b-g | 10x v3 sequencing data from macaque | NEMO | |
| 2b-g | Transcriptomic characterization of cell types in human brain: 10x nuclei v3 (10X159-1 through 10x160-8) | Project Summary | NEMO |
| 2b-g | A Molecular and Cellular Atlas of the Marmoset Brain - 10x v3 (bi005_m1, bi006_m1) | Project Summary | NEMO |
| 2b-g | Transcriptomic cell types in the mouse brain: 10x nuclei v3 (files with prefix pBICCNsMMrMOp) | Project Summary | NEMO |
Panel 2b: Dendrogram reproduced from companion paper (Bakken et al. 2020)
Panels 2f, 2g: Reproduced from companion paper (Bakken et al. 2020)
Panel 2i: Custom UCSC browser of all M1 tracks
Figure 3: In situ cell type identification spatial mapping and projection mapping of individual cells in the MOp by MERFISH
| Panel | Description of data collection | BICCN Project Summary Page | Repository Link |
|---|---|---|---|
| 3 | A molecularly defined and spatially resolved cell atlas using spatial transcriptomics; MERFISH raw data and processed | Project Summary | BIL |
MERFISH data processing pipeline
Figure 4: Correspondence between transcriptomic and morpho-electrical properties of mouse MOp neurons by Patch-seq, and cross-species comparison of L5 ET neurons
| Panel | Description of data collection | BICCN Project Summary Page | Repository Link |
|---|---|---|---|
| 4a | Patch-seq of mouse motor cortex: FASTQ files | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: 10x v2 cells (FASTQ) | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: 10x v3 cells (FASTQ) | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: SMART-seq cells (FASTQ) | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: 10x nuclei | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: 10x nuclei | Project Summary | NEMO |
| 4a | Transcriptomic cell types in the mouse brain: SMART-seq nuclei (FASTQ) | Project Summary | NEMO |
| 4b-g | Morphological reconstructions in SWC | BIL | |
| 4b-g | Patch-seq of mouse motor cortex: electrophysiological traces in NWB format | Project Summary | DANDI |
| 4h | 10x v3 sequencing data from macaque (FASTQ) | NEMO | |
| 4h | Transcriptomic characterization of cell types in human brain: 10x nuclei v3 | Project Summary | NEMO |
| 4h | A Molecular and Cellular Atlas of the Marmoset Brain - 10x v3 | Project Summary | NEMO |
| 4h | Transcriptomic cell types in the mouse brain: 10x nuclei (v3) | NEMO | |
| 4i-k | Electrophysiological traces in NWB format | DANDI | |
| 4i-k | Morphological reconstructions in SWC format | BIL |
Panel h:
Panels a-g:
| Panel | Description of data collection | BICCN Project Summary Page | Repository Link |
|---|---|---|---|
| 5 | Regional DNA methylation profiling of individual projection neurons isolated from the mouse brain | Project Summary | NEMO |
| 5 | Gene Expression Omnibus data | GEO |
Panel c
| Label in Fig. | Full Descriptive ID | Induction date | Harvest date | Tamoxifen dose | Originating Lab |
|---|---|---|---|---|---|
| Lhx2 | Lhx2-CreER; Ai14 | E12.5 | E13.5 | 2 mg/kg body weight | Huang |
| Lhx2 | Lhx2-CreER; Ai14 | E12.5 | P30 | 100 mg/kg body weight | Huang |
| Fezf2 | Fezf2-CreER; Ai14 | E12.5 | E13.5 | 2 mg/kg body weight | Huang |
| Fezf2 | Fezf2-CreER; Ai14 | E12.5 | P30 | 2 mg/kg body weight | Huang |
Panels d-k
| Label in Fig. | Full Descriptive ID | Experiment ID | Originating Lab | Brain Architecture Viewer | BIL link |
|---|---|---|---|---|---|
| PlxnD1 | PlxnD1-CreER;LSL-Flp | 180722 | Huang | Viewer | BIL |
| PlxnD1 | PlxnD1-CreER;LSL-Flp | 180730 | Huang | Viewer | BIL |
| Fezf2 | Fezf2-CreER;LSL-Flp | 180830 | Huang | Viewer | BIL |
| Fezf2 | Fezf2-CreER;LSL-Flp | 190903 | Huang | Viewer | BIL |
| Tle4 | Tle4-CreER;LSL-Flp | 180605 | Huang | Viewer | BIL |
| Tle4 | Tle4-CreER;LSL-Flp | 180816 | Huang | Viewer | BIL |
| Foxp2 | Foxp2-Cre | 190915 | Huang | Viewer | TBD |
| Foxp2 | Foxp2-Cre | 191209 | Huang | Viewer | BIL |
Panel j
| Label in Fig. | Full Descriptive ID | Experiment ID | Originating Lab | Brain Architecture Viewer | BIL link |
|---|---|---|---|---|---|
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E17.5 | 210203 | Huang | Viewer | TBD |
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E17.5 | 210211 | Huang | Viewer | TBD |
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E17.5 | 210301 | Huang | Viewer | TBD |
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E17.5 | 210216 | Huang | Viewer | TBD |
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E17.5 | 210222 | Huang | Viewer | TBD |
| PlxnD1-Tbr2 | Tbr2-CreER;PlxnD1-Flp;dtTA TM E13.5 | 210302 | Huang | Viewer | TBD |
Panel c
| Label in Fig. | Full Descriptive ID | Experiment ID | Originating Lab | SWC (single cells) or 25 um grid (tracer) |
|---|---|---|---|---|
| Rabies | Tlx3-660759241 | 660759241 | Allen | Data link |
| AAV | C57BL/6J-127084296 | 127084296 | Allen | Data link |
| Cux2 L2/3/4 IT | Cux2-IRES-Cre-947242021 | 947242021 | Allen | Data link |
| Nr5a1 L4 IT | Nr5a1-Cre-882407664 | 882407664 | Allen | Data link |
| Tlx3 L5 IT | Tlx3-Cre_PL56-880719308 | 880719308 | Allen | Data link |
| Rbp4 L5 IT+ET | Rbp4-Cre_KL100-948130129 | 948130129 | Allen | Data link |
| Sim1 L5 ET | Sim1-Cre_KJ18-297711339 | 297711339 | Allen | Data link |
| Ntsr1 L6 CT | Ntsr1-Cre_GN220-159651060 | 159651060 | Allen | Data link |
| IT projections | L2/3_Cux2-CreERT2-18453_3456_x24161_y6646 | 18453_3456_x24161_y6646 | Allen | Data link |
| IT projections | L4_Cux2-CreERT2-18864_3338_x3396_y21865 | 18864_3338_x3396_y21865 | Allen | Data link |
| IT projections | L5_AA0271 [A] | AA0271 [A] | MouseLight | Data link |
| ET projections | L5_+MY+TH_Fezf2-CreERT2-182725_3762_x5563_y19178 | 182725_3762_x5563_y19178 | Allen | Data link |
| ET projections | L5_no MY_Fezf2-CreERT2_182725_4080_x6576_y11407 | 182725_4080_x6576_y11407 | Allen | Data link |
| CT projections | L6_AA0649 [A] | AA0649 [A] | MouseLight | Data link |
| CT projections | L6_AA0898 [A] | AA0898 [A] | MouseLight | Data link |
Panels d-i
| Label in Fig. | Full Descriptive ID | Experiment ID | Originating Lab | Brain Architecture viewer |
|---|---|---|---|---|
| PlxnD1 | PlxnD1-CreER;LSL-Flp | 180722 | Huang | Viewer |
| PlxnD1 | PlxnD1-CreER;LSL-Flp | 180730 | Huang | Viewer |
| Tle4 | Tle4-CreER;LSL-Flp | 180605 | Huang | Viewer |
| Tle4 | Tle4-CreER;LSL-Flp | 180816 | Huang | Viewer |