The development of the vertebrate limb is a progressive process characterized by initial induction and patterning, concomitant growth and morphogenesis, and subsequent cell differentiation and tissue formation. Many of these processes are regulated by specific signaling centers and the environment they create. Through both classical approaches and recent molecular studies, we are beginning to understand the roles of these signaling events during limb development. However, several questions still remain and need to be further addressed. In this dissertation, I first examine how signaling molecules regulate the proximal-distal (PD) patterning of the limb. We demonstrate that early limb mesenchyme is initially maintained in a state capable of generating all limb segments by a combination of proximal and distal signals. As the limb grows, the proximal limb is established by exposure to flank-derived signal(s), whereas the distal segments are determined by distal signals when cells grow beyond the proximal influence. Thus, these results support the “two signal model” and contradict the classical view of PD patterning by a clock-based system that was postulated in the “progress zone model”. In the second part of this work, I focus on a later developmental event and study the cell- and non-cell-autonomous function of Sonic hedgehog (Shh) during limb muscle formation. Muscle progenitor cells migrate from the lateral somites into the developing limb, where they undergo patterning and differentiation in response to local signals. We find that Shh patterns limb musculature non-cell-autonomously, acting through adjacent non-muscle mesenchyme. However, Shh functions cell-autonomously to maintain cell survival in the dermomyotome and promote slow muscle differentiation. Finally, Shh signaling is required cell-autonomously to maintain Net1 expression, which in turn regulates directional muscle cell migration in the distal limb. The dissertation ends with three appendices, describing separate studies: first, mechanisms of limb loss in snakes, second, the role of Hippo signaling in limb development, and lastly a collaborative work with Dr. Jérôme Gros on limb morphogenesis. Taken together, this dissertation provides a glimpse into the diverse roles of signaling pathways during various stages of vertebrate limb development.
| Identifer | oai:union.ndltd.org:harvard.edu/oai:dash.harvard.edu:1/10275998 |
| Date | January 2011 |
| Creators | Hu, Jimmy Kuang-Hsien |
| Contributors | Tabin, Clifford James |
| Publisher | Harvard University |
| Source Sets | Harvard University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis or Dissertation |
| Rights | closed access |
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