Max Heiman
@heiman
Associate Professor of Genetics Harvard Medical School, Boston Children's Hospital It should be fun, or what's the point?
Same same. Planted this last year, was really happy it came back after our winter.
I'm glad @carlbergstrom.com posted this. I received one today, and a couple in the last few months, and was wondering if others were receiving them and how they were responding. Overall I've felt like I'd rather risk wasting my time than risk ignoring someone who's genuinely curious.
I saw the story that Barney Frank entered hospice. He was my Representative starting when I was 5, and then again when I moved back as faculty. Here is a signed campaign poster I have from the 1970s (pre-Congress). It hung for years in my dad's office, which was a perpetual mess (like mine is now).
Why does the glial attachment affect calcium in the cilia? Part of the answer may be structural. We found that the guanyl cyclase GCY-9 and the cGMP-activated calcium channel TAX-4 mostly overlap in normal cilia... but become mostly segregated in the absence of the glial attachment.
Now that we had a mutant, we could ask if cilia-glia attachment affects cilia function. Niels Ringstad imaged stimulus-evoked calcium dynamics in BAG neurons with or without the glial attachment. In the cell body, calcium signaling still looked normal - but, in the cilium, not so much.
BUG-1 is a large secreted protein. In mutants lacking BUG-1, neuronal cilia are still present, but they completely fail to attach to their glial partner. BUG-1 localizes at the cilia-glia attachment site, appearing to coat the cilia.
Our mutant led us to a previously uncharacterized gene that we named BUG-1, for (B)AG-(U)RX (g)lia attachment. The screen was done by a postdoc, Leland Wexler, who led the entire project. On a completely unrelated note, here is a picture of Leland's cat Bug.
The power of C. elegans is that you can take a phenomenon you know nothing about and use genetics to discover the underlying molecules. We found that two neuron types (BAG and URX ) use their cilia to attach to a specific glial partner. We isolated a mutant where cilia fail to attach to the glia.
As usual, March has come in like a lion and hopefully it will go out like a lamb. But did you know that's not how it is in other countries? In the Malay peninsula, March comes in like a worm-eating fernbird and goes out like a worm-eating fernbird. Source: amthenfm.wordpress.com/tag/john-bel...
"Snowflakes! What a classic peaceful New England --" Cardinals: "Fill the feeder you lazy @$#%"
Finally, we used regulatory network analysis to find transcription factors (TFs) with targets enriched among pulsatile genes. We found some old friends that are known to control larval timing, like blmp-1, nhr-23, and nhr-25, as well as new suspects who might merit further investigation!
This implies that the cuticle is not a homogeneous mesh at all, but a patchwork that is stitched together from totally different, cell-type-specific components.
But a surprise to me was how little overlap there was between cell types. For example, although many cells are making collagens, they're making DIFFERENT collagens. Same with most genes. In fact, almost half the pulsatile genes we identified were oscillatory in only a single cell type!
Using these new tools, we could ask what kinds of genes oscillate in glia, or skin, or pharynx. For glia and skin it turns out it's mostly #aECM - lots of collagens, ZP domain proteins, and other cuticle proteins. Pharynx has a different kind of cuticle and its oscillatory genes reflect that.
We also developed statistical approaches to quantify how "pulsatile" each gene is within each cell type -- that is, how sharply its expression peaks at one point in time.
We developed quantitative methods to measure how phased each cell is and how oscillatory each cell type is. We found that cuticle-producing cell types like socket glia, seam cells, and pharynx epithelia are highly oscillatory, while non-cuticle-producing ones like neurons and muscle are not.
We had shown that glia make the cuticle #aECM around neuronal cilia. So, we wondered if loops were a transcriptional cycle tied to cuticle synthesis. We used expression data from @labgrosshans.bsky.social to color-code each cell based on when in the larval stage its genes are expressed. Bingo!
In our study, we had begun by trying to do single-cell transcriptomic analysis of C. elegans glia. But, we kept getting loopy patterns in PCA space, like this:
This opens up (literally) a lot of possibilities! I thought the eggshell was needed as a mechanical constraint for morphogenesis. This image of a comma stage embryo happily letting it all hang out in the world with nothing around it is wild!
You will enjoy these hand-drawn tracings from Brenner's notebooks! I would have liked to include them in the intro but it would have been getting a little too historical. libgallery.cshl.edu/items/show/7...
In 1975 "Bohemian Rhapsody" and "Space Oddity" were on the UK top 100, and Ward, Thomson, White, and Brenner published the first reconstruction of the C. elegans sensory anatomy. A short 50 years later, we reconstructed the same neurons and glia in the embryo: doi.org/10.1101/2025...
I took my son and his friend to @wgbh.org 's High School Quiz Show. It is super fun (and free)! It aired this week & you can see us for a nanosecond. As a bonus, the winning coach turned out to be the husband of a @senguptalab.bsky.social grad student whose defense I was on several years ago!
I need a new assistant, this one has an attitude and his emails make no sense.