Dissecting Gene Regulatory Networks Governing Human Cortical Cell Fate - preLights A deep dive into how transcription factors shape radial glia fate and clonal dynamics

10/ Thanks to Manuel Lessi for highlighting a preprint of the study prelights.biologists.com/highlights/d...

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.

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.

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.

Dissecting gene regulatory networks governing human cortical cell fate - Nature Systematic screening of transcription factors reveals conserved mechanisms governing cortical radial glia lineage progression across primates and provides a framework for functional dissecti...

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...

The missing heritability question is now (mostly) answered Not with a bang but with a whimper

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

Dissecting Gene Regulatory Networks Governing Human Cortical Cell Fate - preLights A deep dive into how transcription factors shape radial glia fate and clonal dynamics

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...

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.

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

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.

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.

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.

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.

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 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...

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...

🧠🌟🐭 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🧵

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

Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans Humans exhibit significant phenotypic differences from other great apes, yet pinpointing the underlying genetic changes has been limited by incomplete reference genomes and a reliance on single assemb...

“Intraspecific sequence variation and complete genomes refine the identification of rapidly evolved regions in humans”
New work on HAQERs, by
@rimangan.bsky.social Yanting Luo Craig Lowe @debbysilver.bsky.social @manoliskellis.bsky.social & colleagues
🧪🧬

www.biorxiv.org/content/10.1...

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!

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

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.

"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.

Developmental timing across species: From mechanisms to evolutionary insights Like choreography, development consists of a highly ordered suite of steps and transitions. Modifying developmental tempo can affect final size and composition of tissues, as well as their plasticity…

EMBOMtg Paris May 6-9
@aydoganlab.bsky.social @jamesbriscoe.bsky.social @brunetlab.bsky.social @ebisuyamiki.bsky.social @mwdorr.bsky.social @beyerlab.bsky.social @franckp.bsky.social @janereznick.bsky.social @olmedo-lab.bsky.social @perez-carrasco.bsky.social
meetings.embo.org/event/25-dev...