A novel enhancer near the Pitx1 gene influences vertebrate hindlimb development
Abstract/Contents
- Abstract
- The evolution and development of the vertebrate limb has long fascinated biologists. Vertebrates show a huge degree of diversity in limb form and function, ranging from the heavily modified forelimb of a bat which enables powered flight, to the partial loss of limbs in whales, or the complete loss of limbs in snakes. The mechanisms that produce such differences have been largely unknown. Studying limb modifications that have evolved recurrently can help reveal ecological and molecular factors that shape evolutionary outcomes. One classic example of repeated limb evolution is the loss of pelvic and hindlimb structures, a trait that has independently evolved in many clades, including fish, amphibians, reptiles, and mammals. To date, the molecular basis of hindlimb reduction is still poorly understood in most species. However, in threespine stickleback fish, a combination of genetic and genomic studies has previously identified the Pitx1 gene as a major locus controlling much of the variation in pelvic size in natural species. Recurrent deletion of a pelvic enhancer region upstream of the Pitx1 gene (PelA) is correlated with pelvic reduction in many independently evolved stickleback populations. Despite the widespread use of this enhancer in stickleback populations, the PelA enhancer is not well conserved outside of fish. In my Dissertation research, I have identified and characterized a second pelvic enhancer in the Pitx1 gene, PelB, which is functionally conserved from fish to mammals. The PelB enhancer drives robust reporter activity in the hindlimb autopod of a developing mouse embryo, and the orthologous stickleback sequence is able to drive robust activity in the pelvic spine of a developing fish. In mice, deletion of the PelB enhancer sequence leads to reductions in length of multiple bones in the hind feet. In addition, loss of the PelB enhancer on a genetic background with reduced Pitx1 expression results in complete loss of the patella (kneecap). These experiments confirm that PelB is required for normal hindlimb development, and suggest that mutations in this region might also contribute to evolutionary changes in limb size. To further test whether PelB is altered in species that show natural hindlimb reduction, I compared PelB sequences in pelvic complete and reduced species. While no obviously disabling lesions were observed in whales or manatees, partial loss of PelB was seen in several snake genomes. In addition, I identified one population of pelvic-reduced stickleback fish that has a complex insertion-deletion mutation in PelB. Using functional assays in transgenic sticklebacks, I showed that this naturally occurring mutation causes loss of PelB activity in the developing pelvis, while other expression domains remain intact. These experiments suggest that PelB is an important driver of evolutionary pelvic reduction in some species.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2018 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Thompson, Abbey |
|---|---|
| Associated with | Stanford University, Department of Genetics. |
| Primary advisor | Kingsley, David M. (David Mark) |
| Thesis advisor | Kingsley, David M. (David Mark) |
| Thesis advisor | Fuller, Margaret |
| Thesis advisor | Sherlock, Gavin |
| Thesis advisor | Vollrath, Doug |
| Advisor | Fuller, Margaret |
| Advisor | Sherlock, Gavin |
| Advisor | Vollrath, Doug |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Abbey Thompson. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2018. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2018 by Abbey Carolyn Thompson
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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