The Nervous System is regenerated in Sea Star Larvae Through Reuse of the Embryonic Neural Stem Cell Lineage and Re-activation of Stem Cell Specification

2019-08-29T20:43:12Z (GMT) by Minyan Zheng
Regeneration is a fascinating phenomenon widespread in the animal kingdom that by definition requires cells to reform lost tissues. Despite its wide distribution, the ability of
regeneration varies dramatically among cell types and organisms. The central nervous system, for example, is particularly difficult to regenerate in mammals. In the field of
neural regeneration, arguablely long-lasting interests are the source of the regenerated neurons and the mechanism by which the neural reformation occurs. Transparent larvae of sea stars, Patiria miniata, have an extraordinary regenerative capacity and thereby offer the opportunity to interrogate the sources of neural regeneration and their mechanisms. This study combines BAC transgenesis, cell lineage tracing, molecular analyses and fluorescent microscopy to better identify the cellular sources of regeneration in the sea star larval nervous system. Previously it was known that the serotonergic neurons and some other neurons in the
nervous system of sea star embryos are derived from an embryonic multi-potent neural stem cell lineage expressing the gene soxc. To start characterizing the sources of
regeneration in vivo, I generated a powerful molecular tool to trace cell lineage: a Soxc- Kaede BAC construct that stably labels the Soxc+ cell lineage and effectively differentiates regenerative Soxc expression from developmental Soxc expression through simple photo-conversions. This novel application of BAC transgenesis in larval regeneration sets the technical basis for interrogating the cellular sources of
regeneration. It also holds great potential to be adapted and applied to many other model systems.
This study produced three important findings. First, there is a stem cell population expressing Soxc located at the wound proximal area upon bisection. They consistently
proliferate and eventually become serotonergic neurons and some other neurons in the nervous system of the decapitated larvae. Some of these Soxc+ stem cells at the
wound site are derived from larval Soxc+ cell lineage in the remaining bottom half. And the larval Soxc+ cells are indeed originated from the embryonic Soxc+ stem cell lineage
which generate the serotonergic neurons in embryos. Strikingly, these findings together for the first time demonstrate in vivo that an embryonic multi-potent neural stem cell lineage, which forms the embryonic nervous system, is maintained and populated in the
organism during post-embryo development and is re-used upon bisection to regenerate the nervous system Second, some Soxc+ neural stem cells at the regeneration leading edge are derived from upstream stem cells that are programmed into neural fates, or specification, upon
bisection. Specification of Soxc+ cells occur in embryonic stage but stops in larvae. Decapitation re-initiates the specification events to generate Soxc+ neural stem cells.
These regeneration-specific Soxc+ cells arise from the highly potent Soxb1+ stem cells at the regeneration leading edge. Importantly, the Soxb1+/Soxc+ cells are used in
regeneration to form neurons at the anterior pole.
Last but not least, I observed that de novo Soxb1+ stem cells are specified upon decapitation to regenerate the multiple types of neurons. Soxb1+ cell lineage
contributes to the nervous system in development and during regeneration. The genetic pathway of serotonergic neurogenesis is recapitulated in regeneration. Taken together, these findings shed light on the fundamental mechanisms and cellular basis of neural
regeneration in metazoans.