basic & translational research on CSF-based signaling & choroid plexus • find us
@HMS_Neuro
&
@BostonChildrens
Pathology Dept • // account run by lab members
Overlooked for too many years, the choroid plexus🧠 barrier plays important roles in development, aging, infection, and pathology. Want to know more but don’t have time to read a ton of papers? Check out our SnapShot (by Sivan Gelb) in
@CellCellPress
! 😎
The choroid plexus blood-CSF barrier has remained a mystery for far too long! Our study led by
@NeilCDani1
and Rebecca Herbst, w/ Aviv Regev &
@naomi_habib
, is out today in
@CellCellPress
showcasing a cell atlas & exciting new findings. 1/11
Read it here
How does the 🧠 change between day and night? New work led by
@sciencedame
in
@NatureComms
finds diurnal changes in the choroid plexus and CSF including different translation, secretion, metabolism, and barrier properties. [1/9]
Investigating the choroid plexus has been limited by a lack of tools for in vivo visualization & manipulation. A stunning effort led by recent PhD Fred Shipley
@FreshDipley
and out today in
@NeuroCellPress
showcases a new suite of techniques to fix that!
(1/7) Immune disturbances during development increase susceptibility to neurodevelopmental disorders – but how? Work led by
@Jin_Cui_
& out today in
@Dev_Cell
reveals how the choroid plexus propagates maternal inflammatory signals into the fetal brain.🧠
Celebrating Maria’s promotion to full professor!
“I'm grateful for the effort, enthusiasm, and inspiration of colleagues & friends - esp all lab members & collaborators - for the successes, as well as the silent, yet necessary, failed experiments & challenges along this path.”
🚨Preprint alert -
@ScienceYael
leads work revealing that various maternal exposures, like illness 🤒 or psychedelics 🍄, cause excessive apocrine secretion from embryonic choroid plexus epithelial cells into CSF w/ life-long brain & behavioral impact! 1/
Do immune cells enter the inflamed adult brain via the choroid plexus (ChP)?🤒 Our
@biorxivpreprint
led by
@Huixin_BJ
shows leukocytes crossing the ChP in real time & reveals molecular mechanisms w/ scRNAseq master
@plotfy33
. 1/
ChP-CSF targeted antioxidant therapy protects the brain from toxicity of cancer chemotherapy.🧠
Excited to have this collaborative investigation with Boryana from
@kanareklab
@KanarekNaama
out in
@Neurocellpress
, led in our lab by
@JangAhram
. [1/3]
The lab is thrilled that Maria was recognized w/ Harvard’s prestigious Everett I. Mendelsohn Excellence in Mentorship Award, recognizing that beyond just doing world-class science, she cultivates a world-class training environment for grad students.
Miri’s speech says it all!
The choroid plexus is thought to secrete CSF, but our new study shows that's not always the case! It helps to clear CSF before adult outflow routes mature. Led by Huixin (
@Huixin_BJ
) and Ryann (
@ScienceDame
). Preprint
@biorxivpreprint
.
@BostonChildrens
The choroid plexus constitutes the brain-CSF barrier and has resident immune cells. Our review is now in print with a cover in
@TrendsNeuro
. Led by
@Jin_Cui_
&
@Huixin_BJ
, we explore these special macrophages on the margin of the brain-CSF interface.
We are delighted that our story on neonatal CSF clearance through the choroid plexus is published in
@NatureComms
. New data since the preprint include concentrations of 5 key CSF ions across development.🧠Next time you make aCSF, take a look at TableS1!🤩
The choroid plexus is thought to secrete CSF, but our new study shows that's not always the case! It helps to clear CSF before adult outflow routes mature. Led by Huixin (
@Huixin_BJ
) and Ryann (
@ScienceDame
). Preprint
@biorxivpreprint
.
@BostonChildrens
Intraventricular hemorrhage (IVH) is the leading cause of pediatric hydrocephalus in North America and a devastating complication of preterm birth. Work led by
@csadegh
&
@Huixin_BJ
in
@NeuroCellPress
suggests choroid plexus gene therapy may help. 1/6
The choroid plexus constitutes the brain-CSF barrier and has resident immune cells. Our newly published review (led by
@Jin_Cui_
&
@Huixin_BJ
) explores these special macrophages on the margin of the brain-CSF interface.
Congratulations to our own Ya’el Courtney (
@ScienceYael
) and all the new HHMI Gilliam Fellows!
We look forward to making scientific discoveries while breaking new ground for inclusivity in academia!
#GilliamFellows
@HHMINEWS
Today HHMI announces our largest group of new
#GilliamFellows
as part of our commitment to advance diversity and inclusion in science. Learn more and meet the Fellows:
Choroid plexus epithelial cells regulate CSF production, including secretion of signaling activities for the brain. Our review in Fluids and Barriers of the CNS led by
@JangAhram
details established and new approaches to experimentally target these cells.
Mitochondria produce energy, but are also major signaling hubs. Our review, in
@FrontCellDevBio
led by
@sciencedame
, explores diverse roles mitochondria play as the forebrain specifies, generates neural cells, and connects. Now searchable
@NLM_NIH
PubMed!
Heard of Reissner’s fiber? No? You’re not alone! This bizarre brain structure forms during embryogenesis from SCO-spodin protein & extends from subcommissural organ to spinal cord
NEW:
@Huixin_BJ
et al show developmental importance of SCO-spondin in mice
A very warm welcome to Ya'el Courtney
@ScienceYael
, an incredibly talented Ph.D. candidate in Harvard Program in Neuroscience, as she joins our lab!
@DMSHarvard
@PiN_Harvard
1/3 Choroid plexus barrier properties help protect the brain from the external world. Our recent Preview written with
@Huixin_BJ
highlights newly published work by Pellegrini, et al.
@laupellegrini
in Madeline Lancaster's group
@BrainOrganoid
The lab had some representation today at the Boston Marathon - Congratulations to postdoc
@martaapp
for her incredible accomplishment in qualifying and finishing with a marvelous time! ⭐️⭐️⭐️
MD/PhD student Jill Jones was a medical volunteer along the route!
The editors at
@NatureComms
have put together an Editors’ Highlights webpage of recent research called “From brain to behaviour” - Thank you to Sophie Morgan for choosing work from our lab and
@ScienceDame
on diurnal fluctuations in the ChP and CSF! 🧠⏰
Excited to have this collaborative work with
@KarolKaiser1
and
@bryjalab
out in
@Dev_journal
, led in our lab by
@JangAhram
.
Read for an informative investigation into how transcription factor MEIS1 is a key upstream regulator of Wnt5a in choroid plexus morphogenesis!
CSF ion reg is 🔑 for 🧠 function. We showed that extra ChP NKCC1 clears K+ and H2O from the ventricles during dev & ⬆️ NKCC1 expression treats PHH. Now
@sciencedame
&
@Huixin_BJ
in FBCNS confirm ChP NKCC1 is required to remove CSF K+ in neonates. [1/8]
This week Maria was honored to present the Orbis Pictus Keynote Lecture "Illuminating the brain’s choroid plexus – CSF system" at the Transgenic Technology Meeting, sponsored by
@CZphenogenomics
. Thanks for a great conference!
#ISTT
#TT2022
Congratulations on the hard work and commitment by all applicants to the
@NSFGRFP
award. Today our lab is celebrating graduate student Ya'el Courtney
@ScienceYael
and lab alumni Josh Head
@IrosmJosh
on their awards and lab alumna Aja Claire
@aja_claire
on her honorable mention.🎉
Summer is a time of transition 🌞. We are so glad that we could gather to welcome new lab members, give our best wishes to lab members moving to their next steps, and enjoy each other's company.
Congratulations to our very own Doctor Fred Shipley
@freshdipley
!!! He led a successful thesis defense yesterday, taking us through his incredibly productive and collaborative journey
@andermann_mark
Curious about how the CSF keeps the developing cerebral cortex “afloat”? Check out
@wheremytiara_at
&
@sciencedame
chapter on early CSF production, drainage, fluid dynamics, cilia, and tools to study it.
See the rest of the textbook ⤵️
Neocortical Neurogenesis in Development and Evolution edited by WIELAND B. HUTTNER is out . Superb resource to learn about cortical progenitors; lineages; specification; migration; patterning; cortical regionalisation; folding; disorders; evolution.
Day 2 of
#cshlbbb
is underway! Occurring now - exciting speaker session 3: development, plasticity, and specificity of CNS barriers. Tune in later for session 4: systems, computational, & cell bio as well as a panel discussion about barriers to diversity and, of course, posters!
Congratulations to Miri
@mezawadzki
on her successful qualifying exam this week to officially become a PhD candidate
@BBS_Harvard
!!
Miri's clearly thrilled to be back in the lab, but took a moment to enjoy a celebratory treat delivered by Peter
@pnkalugin
and Ryann
@ScienceDame
"These findings highlight the ChP as an underappreciated brain-blood interface fulfilling functions that are essential for CNS homeostasis during development and adulthood" -
Thank you
@Britta_in_Bern
for this kind preview of work led by
@Jin_Cui_
, hard copy now in
@Dev_Cell
!
Many thanks to Dr. Rajiv Ratan and
@NeuroCellPress
for the preview of our recent paper Jang et al. 2022 with the
@KanarekLab
. A beautiful summary!
"Targeting oxidative distress to treat chemobrain: Go with the choroid plexus-cerebrospinal fluid flow"
We are honored to join our colleagues here at Harvard investigating this devastating disease, and thankful for the support of the 2021 ALS seed grant to help us do so!
Dr. Maria Lehtinen will open the day talking a bit more about the choroid plexus and its importance to brain development and cerebrospinal fluid.
#HydroSymposium
But we didn't stop there!
Demonstrating this technique's versatility, we visualized the motility and mobility of ChP immune cells at baseline and in response to inflammation and injury. This revealed a truly remarkable range of surveillance and defense behaviors like these:
Yesterday lab members enjoyed some time out on the water, kayaking along the Charles River!
Thanks to
@mezawadzki
for spearheading a pandemic-conscious social event.
Thrilled to share our work in the
@wysscoray
lab in collaboration with
@fabiankern13
,
@ZucheroLab
, Andreas Keller and Henrik Zetterberg. We discover a surprising effect of CSF growth factors on oligodendrocyte and memory in the aging hippocampus.
1/13
Looking forward to kicking off
#cshlbbb
meeting today! Many lab members presenting awesome work -
@ScienceDame
speaks to begin session 1 @ 10:45AM EST, sharing abt circadian regulation of the ChP translatome and implications for its secretome, metabolism, and barrier properties
We are excited for the 7th CSH Meeting
@cshlmeetings
on Brain Barriers🧠(virtual) happening April 7- 9, 2021🗓️. Submit your abstract soon (due 1/29/2021). We hope to see you there for a cross-disciplinary exchange of ideas and expertise!
Collectively, these studies show key diurnal changes in the choroid plexus and generate a set of tools that can be used for future real-time study of CSF and choroid plexus. [8/9]
Huge congratulations to lab member
@pnkalugin
for his successful PQE completion and candidacy!
In lieu of our usual in-person celebration, lab members surprised Peter with breakfast from a local bakery before our Zoom lab meeting this morning. (special thanks to
@mezawadzki
)
It was nice to step out of the lab and have a celebratory picnic with everyone this evening. Wishing a special farewell and good luck to Milo (
@mbenedict1822
) as they head to the NIH!
Metabolism in the ChP was also vastly different between day and night. In collaboration with Bory Petrova and
@KanarekNaama
we identified that more metabolites are in the oxidized state at night. CSF metabolites also change with Thyroid Hormone ⬆️ in CSF at night.[6/9]
Happy postdoc appreciation week to the unparalleled Lehtinen Lab postdocs!⭐️You all do so much to cultivate lab wisdom, conduct amazing science, and facilitate countless collaborations.
meme credit: science Twitter
Happy
#PostdocAppreciationWeek
to our wonderful postdocs! They cheerfully pass on valuable knowledge to incoming lab members while conducting brilliant research that drives us forward. Please take a moment to honor them by reading the praise we've collected from lab members:
While continuing our weekly remote meetings, we look forward to partially re-opening our lab this month, with all due precautions. Proud of this incredible group!
Congratulations to Lizz Yimer (
@_Elizzabbethh
), an intern through the
@HarvardGSAS
@DMSHarvard
SHURP program, for completing a summer of successful research and hard work. Wishing you the best of luck in your senior year and throughout grad school applications - you’re a star! ⭐️
Curious about gene expression not covered in the paper? We made our atlases publically accessible via the Broad Institute Single Cell Portal! 2/11
Browse our single cell sequencing atlas
or our single nucleus sequencing atlas.
First, we had to develop micro-dissection approaches to isolate choroid plexus. Take a look at the striking morphologies of explants from the lateral (LV), third (3V) and fourth (4V) ventricle of the developing, adult and aging mouse brain. 3/11
💡 Understanding ChP apocrine secretion opens new avenues for researching developmental disorders & how prenatal factors may contribute, underscoring the relevance of studying the ChP-CSF system as a key player during
#BrainDevelopment
. 8/
Using a ✨new✨TTR-mNEON 🟢 reporter mouse created by
@Huixin_BJ
in the lab and a wonderful collaboration with
@pnkalugin
@PaulSoden18
@andermann_mark
, we observed CSF-TTR in real-time over multiple days. CSF-TTR even cycles when the lights stay out for days. [5/9]
Choroid plexus innate immunity is increasingly recognized for essential roles throughout life and in neurological and infectious diseases. Better understanding of choroid plexus macrophages provides novel, useful perspectives toward harnessing this tissue for disease therapeutics
This approach also allowed the first demonstration that a clinically-relevant dose of the psychedelic compound LSD quickly passes from mother to embryo and dysregulates ChP-CSF signaling. Crucial to consider amidst tremendous enthusiasm for therapeutic psychedelic use! 🍄7/
So proud of
@Huixin_BJ
and her incredible work as a postdoc in our lab! Her hard work, dedication, and cheerful spirit inspire those around her daily 😊
Congratulations on your Hearst Fellowship, it is well-deserved.
First day back in lab, and my first time setting foot in lab as an official member and not just a rotation student! Unboxed some pipettes, met my new desk, and kicked butt on some Choroid Plexus dissections. An amazing day 🧠🔬
The above video shows leukocytes streaming into the CSF across the ChP following inflammation in a mouse model of meningitis. We found that ChP epithelial cells actively recruit these immune cells via a concerted set of signaling steps: 2/
The good news: ChP-targeted gene therapy with antioxidant enzyme SOD3 replenishes CSF’s protective capacity, preventing metabolic damage in the hippocampus (e.g. lipid peroxidation) and behavioral deficits (anxiety behaviors and short term spatial learning & memory). [3/3]
Extremely thankful to PHF
@HydroKids
for renewing their funding support for our lab's research. It's been an honor to get to know the families and we are so happy to have the opportunity to continue our research partnership together!
Single cell sequencing shows that developing choroid plexuses comprise multiple cell types including epithelial, mesenchymal, endothelial, neuronal, glial & immune cells. Mapping the organization of neurons revealed a curious distribution of neuronal cell bodies. 4/11
Apocrine secretion happens in embryonic & adult ChP. We identified a mechanism converging on sustained intracellular calcium signaling and calpain-dependent cytoskeletal remodeling. It can be evoked *in embryos* by a range of maternal stressors!🤰3/
New secretion mechanism 🔬 we built on prior lab work to show that ChP epithelial cells use a high-capacity mode of exocytosis: "Apocrine secretion". Other fluid-producing epithelia do this too, allowing significantly more release than vesicles! 2/
Quite unexpectedly we found expression of blood-brain barrier proteins, such as claudin-5, in choroid plexus across all ages. Mapping claudin-5 expression in explants revealed subsets of vessels that are continuous with adjacent brain regions. 9/11
We found that, like in other epithelia, dynamic cellular functions of the ChP are associated with changes in intracellular calcium. We established a relationship between serotonergic agonists, intracellular calcium, and ChP secretion events like those seen in this video:
We found SARS-CoV-2 cell entry proteins expressed in multiple choroid plexus cell types across ventricles of the developing, adult and aging brains. Our results highlight the pressing need to better understand neuroimmune functions of the choroid plexus brain barrier. 8/11
On Sunday, I graduated Cum Laude with Honors from Davidson College with a BS in Neuroscience! Many people helped me reach this point, but I especially want to thank my parents and Dr. Barbara Lom for their constant support.
Next stop: Dr. Maria Lehtinen’s lab
@BostonChildrens
@JangAhram
et al. reports that cancer chemotherapy MTX damages the choroid plexus and cerebrospinal fluid (CSF) by oxidative stress. The impoverished CSF propagates MTX toxicity BUT - this finding also offers hope - can serve as a conduit for therapy. [2/3]
Today we celebrate an enjoyable and productive summer with
@aja_claire
building new knowledge and new relationships in the SHURP program at
@DMSHarvard
. We look forward to future collaborations and wish her well next year
@SalveRegina
and beyond!
(3/7) We developed live imaging and analysis approaches for monitoring ChP macrophage behaviors in vivo in the embryonic brain, revealing incredible motility and mobility of these cells already very early on! Check out some example cells (green)(VIDEO).
2/3 Pellegrini, et al.
@laupellegrini
report the successful creation of human ChP organoids that produce a cerebrospinal fluid-like secretion and recapitulate barrier functions.
Our study supports that the ChP acts as an immediate responder to intraventricular blood by boosting CSF clearance capacity in the acute phase of IVH, & that this NKCC1-dependent mechanism can be targeted by AAV therapy in pediatric and adult models. 5/6
Congratulations to Dean Campagna for being recognized with the inaugral "Spirit of Pathology Research Award"! Well deserved!
@BostonChildrens
#BCH_Pathology
Beyond the core cell types we identified a glia-like precursor population that gives rise to choroid plexus epithelial cells & neurons in the developing hindbrain. Shown here is a trajectory analysis that helped us map precursor & differentiated cell states in the paper. 5/11
As an organizing lab for
@cshlmeetings
Brain Barriers 2021 (Apr 7-9), we are happy to share a tangible commitment to increasing equity by reducing registration to $25 for individuals from US/Canada minority serving institutions or low income countries.
New Harvard nanocourse covering CSF metabolite profiling in the context of chemotherapy, led by Naama
@KanarekNaama
, Loren
@LorenWalensky
, and myself. This March 5 & 26. Sign up below!
Our findings also highlight a straightforward approach to evaluating the potential for compounds to disrupt the ChP-CSF system: immediate early gene expression and apocrine structures in embryonic ChP (30’ after maternal exposure!) Here we show sensitivity to TRPM3 agonists. 6/
(5/7) Elevated CCL2 produced by ChP and secreted into the CSF can ultimately disrupt cerebral cortical development. Considered with other work, these findings support CCL2 and ChP as contributors to pathologies associated with neurodevelopmental diseases.