# The non-canonical thioreductase Tmx2b is essential for neuronal survival during zebrafish embryonic brain development

## TL;DR

Tmx2b is essential for post-mitotic neurons in the developing zebrafish brain, and its loss causes cell death linked to calcium imbalance.

## Contribution

Tmx2b is identified as a conserved, neuron-specific regulator critical for embryonic brain development.

## Key findings

- Tmx2b deficiency causes post-mitotic neuron death in the zebrafish brain after 3 days.
- Neuronal progenitor and radial glial cells remain unaffected in tmx2b mutants.
- Calcium levels in neurons are persistently elevated in tmx2b mutants, suggesting a role in calcium homeostasis.

## Abstract

Biallelic variants in thioredoxin-related transmembrane 2 protein (TMX2) can cause a malformation of brain cortical development characterized by microcephaly, polymicrogyria and pachygyria by an unknown mechanism. To investigate and visualize how TMX2 loss disrupts brain development in vivo, we generated zebrafish deficient for TMX2 ortholog tmx2b, which during the first two developmental days showed normal brain developmental hallmarks. From 3 days onwards, however, tmx2b mutants had no locomotor activity; this was accompanied by cell death in the brain, but not in other organs or in the spinal cord. Strikingly, cell death in tmx2b mutants occurred specifically in post-mitotic neurons within a ∼1.5-h timeframe, whereas neuronal progenitor and radial glial cells were preserved, and could be suppressed by inhibiting neuronal activity. In vivo calcium imaging showed a persistent ∼2-fold increase in calcium in neurons after the onset of cell death. This suggests that calcium homeostasis underlies the tmx2b mutant brain phenotype. Our results indicate that TMX2 is an evolutionarily conserved, protective regulator essential specifically for post-mitotic neurons after their differentiation in the vertebrate embryonic brain.

Summary: The non-canonical thioreductase Tmx2b is an evolutionarily conserved, protective regulator essential specifically for post-mitotic neurons after their differentiation in the vertebrate embryonic brain.