RF1 - Nowakowski 1RF1MH121268-01

Mapping Developmental Lineage Relationships in the Cerebral Cortex

An outline of the major questions addressed in this project – do radial glia become restricted during development to give rise to unique neuronal lineages? How are differences in progenitors manifest linked to differences in cortical areas? What are the lineage relationships between spatially related cells in the adult?


This project seeks to utilize novel lineage tracing technologies to explore the developmental origins of the brain at the level of individual cell types and distinct functional areas. To investigate these developmental relationships, the Nowakowski lab will implement a suite of high-throughput lineage tracing tools. In the first approach, relationships between distinct cellular subtypes in the brain will be explored using highly diverse DNA barcodes to identify whether or not they are born from distinct progenitors. Lineage relationships will be combined with single-cell transcriptomic analyses to determine both the developmental identity and the terminal fate of the cells. Temporal relationships between cell types that share a lineage history will also be investigated using dynamic, continuously editing barcodes. In the second goal of this project, developmental trajectories will be mapped to and contexualized with their spatial identity. This will enable a clear understanding of how developmentally-related cells are organized within the cortex and across distinct functional areas by employing novel in-situ sequencing techniques that allow for a spatial readout of lineage history. This project will build on existing knowledge of the vast diversity of cell types and functions in the mature cortex and provide a developmental perspective on how these cells arise and organize themselves during development, filling in an essential gap in knowledge that currently exists between the two fields. The technologies generated and utilized in this project will provide widely-applicable tools for a range of developmental questions that will allow for characterization of lineage relationships at scales ranging from the whole brain to individual cells.

Project Leadership

Tomasz Nowakowski, Ph.D. (Principal investigator)
Assistant Professor, Anatomy
University of California, San Francisco


Jonathan Weissman, Ph.D. (Collaborator)
Professor, Cellular Molecular Pharmacology
University of California, San Francisco


Bosiljka Tasic, Ph.D. (Collaborator)
Allen Institute for Brain Sciences


Rafael Gomez-Sjoberg, Ph.D. (Collaborator)
Director of Bioengineering
Chan-Zuckerberg Biohub


Maximilian Haeussler, Ph.D. (Collaborator)
Research Scientist
University of California, Santa Cruz


Nir Yosef, Ph.D. (Collaborator)
Associate Professor, Electrical Engineering and Computer Science
University of California, Berkeley


Jay West, Ph.D. (Collaborator)
President, CEO, Co-founder

Project Data Types

  • Transcriptomic analysis of cortical regions in mouse using 10X single-cell sequencing
  • Immunohistochemical analysis of mouse cortical cell types
  • In-situ sequencing of lineage barcodes and marker genes
  • Spatial transcriptomics

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