U01 - Kriegstein 1U01MH114825-01

A Cellular Resolution Census of the Developing Human Brain

The Kriegstein U01 aims to create a spatiotemporal single cell resolution map of the developing human neocortex to establish how many distinct cell types are present and to unravel their complex developmental history.  Analysis will be built on a multimodal classification of cell types based on transcriptomic signatures but complemented where possible by physiological and epigenetic features.  Transient cell populations present only during developmental stages will be examined, along with retaining positional information for all cell data to create a developmental cell atlas that plots the diversity of cell types according to their locations in the growing human brain.  The Kriegstein group has developed innovative strategies for massively parallel profiling of molecular and physiological properties of primary human cortical cells using droplet based capture technologies, high content microscopy, and paired physiological responses to transcriptional state. An integrated cellular survey of developing human brain will be conducted in specific regions of the cortex, as well as in the striatum, thalamus, hypothalamus and cerebellum, and single nuclei sequencing will be used to unlock developmental time points that have been traditionally difficult to study. The aims of this project will shed light on the origins of cellular diversity in the human cortex.    

 

  • Single cell RNA-sequencing will be used to interrogate how neurogenesis and gliogenesis proceed and give rise to key cell types in the developed brain.  
  • The Kriegstein group’s developmental approach to the human brain cell atlas provides an opportunity to characterize transient cell populations that appear early in development in the marginal zone and subplate regions, and disappear at neonatal stages. These cell types are presumed to play important roles in establishing brain architecture and function, but they remain poorly characterized in developing human brain.  
  • Transcriptional states are a powerful tool for cell type identification, but they do not capture the entire complexity of molecular features. This project will profile cell-specific agonist responses and chromatin state that reflect heterogeneity within defined transcriptional classes.  

Project Leadership

Dr. Arnold Kriegstein (Principle Investigator) 
Director, Developmental and Stem Cell Biology Program 
Professor, University of California San Francisco 
https://profiles.ucsf.edu/arnold.kriegstein 

 

Dr. Eric Huang (Co-Principal Investigator) 
Professor, University of California San Francisco 
https://profiles.ucsf.edu/eric.huang 

 

Dr. Tomasz Nowakowski (Co-Investigator) 
Assistant Professor, University of California San Francisco 
https://profiles.ucsf.edu/tomasz.nowakowski 

 

Dr. Alexander Pollen (Co-Investigator) 
Assistant Professor, University of California San Francisco 
https://profiles.ucsf.edu/alex.pollen 

 

Dr. Jim Kent (UCSC Collaborator) 
Research Scientist, University of California Santa Cruz 
https://users.soe.ucsc.edu/~kent/ 

 

Dr. Aparna Bhaduri (Leading Single-Cell sequencing) 
Postdoctoral Scholar, University of California San Francisco 
https://profiles.ucsf.edu/aparna.bhaduri 

 

Dr. Dmitry Velmeshev (Leading Single-nuclei sequencing) 
Postdoctoral Scholar, University of California San Francisco 
https://profiles.ucsf.edu/dmitry.velmeshev 

 

Dr. Simone Mayer (Leading Physiology Studies) 
Postdoctoral Scholar, University of California San Francisco 
https://profiles.ucsf.edu/simone.mayer 

 

Dr. Maximilian Haeussler (UCSC Collaborator) 
Research Scientist 
http://hgwdev.soe.ucsc.edu/~max/ 


Project Data Types

  • Single-Cell sequencing (cortical and sub-cortical brain regions) 
  • Single-nuclei sequencing (postnatal and early adolescent time points) 
  • Single-cell physiology data (single cell calcium signaling and paired transcriptome profiles have been collected from neurogenic stages of development. An additional several thousand profiles on coverslips with calcium signaling have also been collected.) 
     

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