Comparative analyses suggest that stem-cell based regeneration–including regeneration of the central nervous system (CNS)–is likely an ancestral feature that was lost in mammals and other taxa. Research into species capable of CNS regeneration therefore has the potential to uncover mechanisms that are difficult to extract from studies in mammalian systems.

The annelid worm Platynereis dumerilii has unique value for studying stem cells both in neural development and neural regeneration: On the one hand, the trunk central nervous system of this invertebrate species was demonstrated to be set up in molecularly distinct columns that are strikingly similar to the columns generated by the morphogen-dependent patterning of the vertebrate neural tube, thereby lending support to the notion that bilaterian central nervous systems are deeply conserved. On the other hand, neural regeneration in this species strongly depends on developmental timing: When amputated, young animals induce larger regenerates than older animals, and both posterior growth and regeneration capacity are completely reduced in fully grown adults. This suggests that the responsible system is subject to an ageing process, either by direct regulation of the involved stem cells, by affecting the expansion and proliferation of the generated progenitor domains, or their differentiation.

Platynereis has over the past years advanced into a functional model system with advanced opportunities for genetic manipulation and experimentation, including transgenesis, targeted mutagenesis, dissociation, and single-cell sequencing. Recent progress in deciphering molecular determinants of the regenerative-reproductive switch offers a unique chance to dissect the key molecular steps involved in neural lineage commitment in a “vertebrate-type” invertebrate CNS, both during development and during regeneration.

The Raible group at the Max Perutz Labs is working together with the von Haeseler, Kicheva and Hippenmeyer groups to integrate results of single cell profiling and sparse lineage labeling experiments to derive individual differentiation trajectories in the growing and regenerating CNS and probe their changes along developmental time to detect molecular signatures of ageing. Together with the Tanaka group we will assess the role of specific hormone sensors in modulating stem cells in this process to explore mechanistic principles also in the axolotl system.

These experiments will provide insight into fundamental principles of the impact of developmental timing on stem cell-based regeneration of animal central nervous systems.

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