Date of Award

12-31-2021

Document Type

Campus Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biology/Molecular, Cellular, and Organismal Biology

First Advisor

Catherine D. McCusker

Second Advisor

Alexey Veraksa

Third Advisor

Kellee Siegfried

Abstract

Limb loss has a profound effect on a person’s health and quality of life. While humans cannot regrow limbs, other species have remarkable regenerative abilities. The axolotl (Ambystoma mexicanum) is one of the few tetrapod species capable of regenerating complete limbs. One important yet understudied aspect of limb regeneration is the mechanism by which the regenerated structure grows to the size that is proportionally appropriate to the size of the animal. In larger animals, it is apparent that growth of the limb regenerate occurs in two stages. The first stage includes the formation of the early regenerate (the blastema) and its growth, patterning, and differentiation into the missing limb structure. This initial limb regenerate is proportionally very small in size relative to an uninjured limb. During the second stage of growth, the “tiny limb” grows at a rapid rate relative to the rest of the animal, until it reaches the appropriate size. The mechanisms regulating growth of the tiny limb are not known. I have discovered that size during limb regeneration is regulated through systemic signals. I have also observed that the abundance of innervation is increased in the tiny limb staged regenerate. Previous evidence also correlates innervations with tissue growth in the regenerate. Thus, nerve signaling is a systemic factor that could regulate growth of the tiny limb. I have found that it is required for the elevated cell proliferation and repressed cell death occurring during regeneration. Furthermore, neurons supplying tiny limbs express elevated levels of growth factors, such as BMPs. Lastly, when BMP signaling is inhibited during the tiny limb stage of regeneration, limb outgrowth is significantly hindered. These data suggest that nerves innervating the limb regenerate act through BMP signaling to drive the growth necessary to reestablish limb proportionality during regeneration. Further studies are necessary to determine the specific mechanism of BMP regulation of limb size.

Comments

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