Congenital or acquired developmental disorders have devastating effects on the quality of life of a person and their ability to participate in society. However, we still have not been able to find a cure or a reason behind many of the prevalent growth defects. Understanding cellular and molecular mechanisms that trigger and mediate developmental robustness; that is the ability to maintain organ size, pattern and function even in the face of perturbations, can aid the advancements of targeted therapies for developmental disorders. Interestingly, most vertebrate organs show some ability to catch-up after transient growth impairment. However, the molecular mechanism underlying this phenomenon is still unknown.
To shed light in this process, we have developed a genetic system to express Diphtheria Toxin A (DTA) during mouse development with high spatiotemporal control. We generated transient unilateral cell death in the cartilage regions that form the scaffolds of the long bones at embryonic day 13.5, affecting exclusively the left-limb cartilage, leaving the right limb as internal control. This created left-right limb asymmetry 3-4 days post-injury (dpi), but the left limb showed signs of recovery already at 6dpi, catching up with the right one.
To gain mechanistic insight into this compensatory process, we have performed bulk regulomic and, multi-candidate mRNA in situ hybridisation at several stages post-injury. Our working model is that the “SOS” signal from the injured cartilage cells evoke the secretion of a specialised glycoprotein that is then sensed by a novel transmembrane receptor in the uninjured cells which results in mTORC1 activation. Moreover, these studies suggest that cell communication occurs not only from the injured cartilage to the surrounding tissues but also to the other limb, and potentially other organs. Along these lines, our collaborators were able to identify similar responses taking place in compensatory renal hypertrophy upon unilateral nephrectomy, suggesting that these signalling pathways are co-opted for multiple regenerative responses and act systemically, enhancing the injury-response ability in the rest of the body. In the long term, these findings are expected to provide the groundwork for new treatments for growth disorders such as pseudoachondroplasia and cartilage injuries (both involving ectopic cell death in the cartilage), and renal disorders such as chronic kidney disease.