Hox gene regulation of body size and asexual reproduction underlie regenerative abilities

Abstract The ability of certain animals to regenerate their cells and tissues has long been a subject of interest for biologists due to its relevance to animal development and regenerative medicine. However, we still don't fully understand why some animals regenerate so well, while others cannot. From a holistic perspective, the loss of

regenerative capacity in vertebrates correlates with the evolution of larger and more complex body plans as well as the loss of asexual reproduction. However, it's unclear how body size or anatomical complexity affects regenerative processes, and the role of asexual reproduction in this process is unknown. This knowledge gap

centers on a fundamental principle underlying the differential regenerative properties of animals and their tissues. Hox genes are conserved transcriptional regulators key to the evolutionary diversification of body plans. Although Hox genes have been extensively studied in animals with limited regenerative capabilities, their

functions in animals capable of whole-body regeneration are not well understood. A better understanding of Hox gene functions in highly regenerative organisms could provide valuable insight into the body plan features that underlie the retention and modification of regenerative abilities. As a trainee, I have discovered that Hox genes regulate asexual reproduction in planaria, a flatworm that

can regenerate its entire body. This invertebrate model's potent regenerative abilities and amenability to advanced molecular analysis and large-scale gene interference screens make it ideal for studying the fundamental mechanisms of animal regeneration. Our recent preliminary data reveal a new role of Hox genes in

limiting the body size of planarians. Taking advantage of this finding, we generated animals five times their normal size and discovered that planarian regenerative abilities cannot functionally scale in an expanded body plan. Finally, we have identified genes with dual functions in both whole-body regeneration and asexual

reproduction from a large RNAi screen of transcriptional regulators, which lays the foundation for uncovering a shared gene regulatory network linking these processes. Through the mechanistic dissection of how Hox genes support planarian whole-body regeneration, I aim to expand our understanding of the functions of these key developmental genes while providing important insight

into the fundamental principles distinguishing regenerative versus non-regenerative body plans. This work has the potential to enhance our understanding of the permissive factors underlying tissue regeneration and to inspire and inform novel approaches to improving human health.