iiinova — where your digital self keeps evolving

9/ We hope our study will provide a framework for functionally studying how disease and evolution shape human cortical development.

8/ Dual repression of ARX and LMO1 partially rescued the ectopic interneuron cellular state.

7/ We found a postmitotic role for ARX in safeguarding interneuron identity. Without ARX, the cells display “ectopic" subtype identity, characterized by LMO1 upregulation.

6/ Multiple transcription factors converge on shared downstream targets - these hub effector genes are often linked to neurodevelopmental and neuropsychiatric disorders, suggesting disorder related genes are more well connected in the TF regulatory networks.

5/ We also identified NR2E1 and ARX that have opposing roles in regulating the balance of excitatory versus inhibitory neurogenesis. By combining single cell lineage tracing with Perturb-seq, we discovered their roles in balancing RG lineage plasticity and progression.

4/ We identified multiple TFs with new roles in cortical neurogenesis, including ZNF219 that represses neural differentiation.

140

3/ We used CRISPRi to repress 44 transcription factors in human radial glia and then measured the consequences on neurogenesis using single cell RNA sequencing.

140

2/ Radial glia are multipotent progenitor cells that give rise to most cells in the cortex, including excitatory neurons, oligodendrocytes and astrocytes, as well as olfactory bulb interneurons and a recently characterized population of cortical interneurons.

140

Dissecting gene regulatory networks governing human cortical cell fate - Nature

1/ Our new study, led by Jingwen Ding, examines the role of transcription factors during human neurogenesis to identify gene regulatory networks influencing cell fate, maturation, and subtype specification www.nature.com/articles/s41...

nature.com

Systematic screening of transcription factors reveals conserved mechanisms governing cortical radial glia lineage progression across primates and provides a framework for functional dissecti...

76828

Reposted by Alex Pollen

Sasha Gusev @sashagusevposts.bsky.social · 21/11/2025

I wrote a little bit about the "missing heritability" question and several recent studies that have brought it to a close. A short 🧵

theinfinitesimal.substack.com

The missing heritability question is now (mostly) answered

Not with a bang but with a whimper

14353167

Reposted by Alex Pollen

preLights @prelights.bsky.social · 18/11/2025

A deep dive into how transcription factors shape radial glia fate and clonal dynamics. Manuel Lessi: this work “combines the strengths of primary cultures and pooled CRISPRi perturbation”. #preprint Jingwen Ding & team @brainevodevo.bsky.social #preLight ⬇️ prelights.biologists.com/highlights/d...

prelights.biologists.com

Dissecting Gene Regulatory Networks Governing Human Cortical Cell Fate - preLights

A deep dive into how transcription factors shape radial glia fate and clonal dynamics

071

This study was supported by NIH funding and an excellent team of collaborators, including @fennak.bsky.social, @mallarinolab.bsky.social, @searslab.bsky.social, Mike DeBerardine, Aunoy Poddar, Miguel Turrero Garcia, and the Paredes, Harwell lab and Berke labs.

Collectively, the broad pattern of inhibitory neuron conservation suggests that, on the mammalian timescale, evolution modifies the brain by ‘teaching old cells new tricks’, rather than inventing novel cell types early in development.

131

Together, we conclude the TAC3 initial class is conserved across placental mammals, but modifies its gene expression and distribution throughout evolution.

131

In adult mouse, we identified a rare subpopulation of Th interneurons which expresses residual Tac2 (TAC3). Using the Allen institute’s Merscope data, we find this rare Tac2-expressing population is spatially restricted to the ventromedial striatum.

111

Through integrated analysis of adult mouse, marmoset, and human striatal inhibitory neurons, we confirmed the homology of Th interneurons in adult mouse and TAC3 interneurons in the adult primate.

111

Surprisingly, we find that the population was hiding in plain sight, but disguised by the loss of TAC3 (called Tac2 in mouse) and gain of Th expression, indicating an unappreciated homology between rodent Th and mammalian TAC3 striatal interneurons.

131

Given the conservation of this initial class in Laurasiatherians and marsupials, we next investigate the Glire lineage (rabbit, naked mole rat, rat, mouse), as the population was reported missing in mouse.

111

Although the TAC3 initial class is conserved to marsupials (opossum and sugar glider), we observe turnover of signaling pathway genes across multiple timescales, and an additional migratory destination in Laurasiatherian (pig and ferret) cortex

Through integrative analysis, we find that initial classes of inhibitory neurons are conserved across placental mammals. Surprisingly, this conservation includes the MGE-derived TAC3 initial class, which was previously thought to be a primate-specific striatal interneuron population

We begin by performing cross-species analysis of developing initial classes of both striatal and cortical inhibitory neuron populations by integrating single cell sequencing data from 8 mammals, spanning from primates to marsupials.

Conservation and alteration of mammalian striatal interneurons - Nature

Our new manuscript, led by Emily Corrigan, examines inhibitory neuron diversity across approximately 160 million years of evolutionary divergence, as part of BRAIN Initiative Cell Atlas Network (BICAN) developing brain atlas package: www.nature.com/articles/s41...

nature.com

An analysis of cell-type diversity in brain samples from a variety of mammalian species, both during development and in adult animals, reveals that the TAC3 initial class of striatal interneurons is c...

26624

Reposted by Alex Pollen

Kelsey Tyssowski @kelseytea.bsky.social · 22/10/2025

🧠🌟🐭 Excited to share some of my postdoc work on the evolution of dexterity! We compared deer mice evolved in forest vs prairie habitats. We found that forest mice have: (1) more corticospinal neurons (CSNs) (2) better hand dexterity (3) more dexterous climbing, which is linked to CSN number🧵

19380124

Reposted by Alex Pollen

Catherine Dulac @dulaclab.bsky.social · 21/10/2025

I am thrilled to share our latest work: we identified a population of central amygdala neurons that promote the earliest and perhaps most important social behavior: pup suckling!... We also developed new tools for pup neuroscience Work by @Jeff Moore now at USC, a collaboration with @Sam Pfaff lab

210329

Alex Pollen @brainevodevo.bsky.social · 24/09/2025

Grateful for @enardhellmannwg.bsky.social labs to host @nkschaefer.bsky.social and exchange ideas about village cell culture and human-specific evolution with experts at LMU Munich, including the Hellman and Enard labs as well as @boyanbonev.bsky.social!

030

Reposted by Alex Pollen

Enard/Hellmann Lab @enardhellmannwg.bsky.social · 19/09/2025

We’re excited to host @nkschaefer.bsky.social from the Pollen Lab @brainevodevo.bsky.social, UCSF! He’ll present Cellbouncer, a new bioinformatic tool for pooled single-cell processing that yields insights into hominid evolution 🧬 More about the lab 👉 www.pollenlab.org

161

Reposted by Alex Pollen

Carl T. Bergstrom @carlbergstrom.com · 06/06/2025

"Sources said the administration is specifically considering a full termination of federal grant funding for the University of California and California State University systems." Pure vandalism. This could never happen in a country with functioning checks and balances.

cnn.com

Trump preparing large-scale cancellation of federal funding for California, sources say | CNN Politics

The Trump administration is preparing to cancel a large swath of federal funding to California, an effort which could begin as soon as Friday, according to multiple sources.

651116354

Congratulations to Nathan for conceiving and designing this unified demultiplexing toolkit!

072

We hope that CellBouncer will accelerate population-scale single cell genomic analyses, improve ambient RNA correction, and enable new experimental designs not previously possible.

000

Surprisingly, cells with mitochondria from two hominids show evidence for apoptotic pathway induction, reduced mRNA expression, and less efficient processing of polycistronic mitochondrial transcripts, revealing recently evolved incompatibilities in the hominid lineage.

100

Our analysis revealed that human and bonobo mitochondria typically outcompete those from chimpanzee, but we also identified a fraction of cells where chimpanzee mitochondria win and cells where both mitochondria survive.

110

We put CellBouncer to the test with a challenging demultiplexing problem of assigning 24 hominid tetraploid composite cell lines generated by Bryan Pavlovic to both individuals-of-origin and identifying the mitochondrial haplotypes present. www.biorxiv.org/content/10.1...

1113

CellBouncer tools were crucial for our study of dopaminergic evolution that included ventral midbrain organoids with up to 17 individuals from 4 species, led by Sara Nolbrant, @jenellewallace.bsky.social, and Jingwen Ding: www.biorxiv.org/content/10.1...

051

For full details on how the tools work, see: bsky.app/profile/nksc...

100

Finally, CellBouncer harmonizes independent metrics for doublet identification to produce a global doublet rate

100

CellBouncer assigns sgRNAs and other perturbation tags to cell-of-origin, accounting for low coverage and increased tag background

100

CellBouncer also provides independent validation methods for statistical confidence in assignments, including a tool for determining individual proportion in bulk (and pseudobulk) RNA-seq data

100

Importantly, CellBouncer uses sequence variation as an external ground-truth for ambient RNA determination, improving individual-of-origin assignments and enabling cell level corrections, while providing insights into the nature and sources of ambient RNA.

100

Genotype-free assignments for an unknown number of individuals by discovery of mitochondrial haplotypes

110

Individual-of-origin assignments for cells that account for deep population structure, scale across large SNP sets, and are robust to ambient RNA

100

Alignment-free rapid species assignments with an underlying statistical model

100

Pooled processing or culture of cells provides a promising avenue to connect human genetics and single cell genomics but creates new bioinformatic challenges.. CellBouncer provides 7 integrated tools to accelerate pooled experiments, including:

100

A major goal for our group and the field is to connect naturally occurring genetic variation to cellular phenotypes, across individuals, species, cell types, stimuli, and genetic perturbations.

100