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Science1 publisher2 min readPublished

Stanford's Loh lab traces the front and back of the brain to two separate progenitor cells

Kyle Loh's group reports that forebrain and midbrain neurons descend from OTX2 progenitors while hindbrain neurons descend from GBX2 progenitors. Starting from the right cell, they grew human hindbrain motor neurons.

The Scientist · Science desk

Photograph accompanying Stanford's Loh lab traces the front and back of the brain to two separate progenitor cells
Photo: newscientist.com

What happened

  • In mouse embryos, Kyle Loh's Stanford group found that the brain develops from two types of early progenitor cell, proliferative cells with a limited capacity to self-renew.
  • One population expresses the gene OTX2 and gives rise to forebrain and midbrain neurons; the other expresses GBX2 and gives rise to hindbrain neurons.
  • Experiments on human cells in a dish showed the same division, with hindbrain neurons and forebrain/midbrain neurons coming from different progenitors.

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Why it matters

  • capability ALS and spinal muscular atrophy researchers get a dish source of the cell type those diseases attack, which Loh says should assist work on both.
  • constraint Any protocol that produced hindbrain-like cells from forebrain and midbrain progenitors now needs its cell identity rechecked before results built on it hold.
  • decision Groups studying how GLP-1 appetite suppression works have to decide whether to keep inferring from mouse hindbrain or build human GBX2-lineage cells to test it directly.

The finding came out of a failure. "It was actually a summer student's failed experiment that got us into this," Kyle Loh of Stanford University told New Scientist [9]. Labs trying to grow hindbrain neurons had typically started from progenitor cells destined to become forebrain and midbrain neurons, and, according to Loh, that does not work [10]. Starting from the GBX2 population instead, his group grew functional human hindbrain motor neurons in a dish, which the report describes as a first [11].

That matters for two diseases. ALS is the most common motor neuron disease, and both ALS and spinal muscular atrophy cause speech and swallowing difficulties because they affect the hindbrain [13]. Loh said the easier route to hindbrain neurons should assist research into both [15]. The mouse work was done in embryos, the human work in culture [4][7]. New Scientist's report does not name the journal or give the number of embryos staged.

The evolutionary claim rests on a different kind of evidence. Chicken, zebrafish and acorn worm embryos showed the same two-progenitor pattern [16], and on that basis the researchers suggest the two-origin arrangement is at least 550 million years old [17]. Jellyfish, which have two separate nervous systems, diverged from our lineage 600 to 700 million years ago [18]. Subtract one figure from the other and any merger has to sit between 550 and 700 million years ago, a bracket as much as 150 million years wide [1].

"Our research suggests that evolution took two existing neural systems and pushed them together spatially," Loh said [2]. He put the design cost plainly: "Having the brain as one organ would probably be more efficient, but we rely on this primordial way to make the brain as two separate pieces" [3]. On what the split may have bought, with the hindbrain handling breathing, sleeping, eating and the beating of the heart [12], he said "evolution could play around with the forebrain, and make mistakes and give rise to all the fancy things like memory and creativity" [20]. Those are hypotheses about selection, and what the experiments measured was progenitor identity.

The other use Loh named is pharmacological. GLP-1 drugs including Ozempic and Wegovy suppress appetite in mice by acting on the hindbrain [14], and Loh said human hindbrain neurons in a dish should let researchers investigate how those drugs work in people [15]. The cell type his group reports making is the motor neuron [11], which is what ALS and spinal muscular atrophy attack [13]; the appetite question would need other hindbrain neurons grown from the same GBX2 lineage.

What to watch

  • Whether other labs reproduce functional human hindbrain motor neurons starting from GBX2-positive progenitors.
  • The publication itself: the journal, the number of embryos staged, and how the motor neurons were assayed as functional.
  • Whether the two-progenitor split turns up in lineages beyond mouse, human, chicken, zebrafish and acorn worm, which is what would firm up the 550-million-year floor.
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