05/18/2026
By Irma Silva

The Kennedy College of Sciences, Department of Biological Sciences, invites you to attend a Ph.D. Dissertation Defense in Applied Biology by Sean Driscoll entitled: “Alternative Splicing as a mechanism of gene dosage mediation during limb morphogenesis.”

Candidate: Sean Driscoll
Date: Wednesday, May 27, 2026
Time: 3:30-5:30 p.m.
Location: Olsen 503

Committee members:

  • Jennifer Fish, Assistant Professor, University of Massachusetts Lowell
  • Frederic Chain, Associate Professor, University of Massachusetts Lowell
  • Teresa Lee, Assistant Professor, University of Massachusetts Lowell
  • Axel Newton, Research Fellow, Comparative Genomics, University of Melbourne, Australia

Title: Alternative splicing as a mechanism of gene dosage mediation during limb morphogenesis

Brief Abstract:
Gene regulatory networks (GRNs) governing limb development are highly conserved throughout tetrapods; however, the resulting morphology is incredibly diverse. Differences in the amount and temporospatial dynamics of gene expression are thought to underlie this variation. Previous work has shown that alterations to regulatory sequences and epigenetic modification contribute to evolutionary differences in gene expression. I hypothesize that alternative splicing (AS) is an additional mechanism contributing to limb GRN differences. AS produces multiple protein isoforms from a single precursor mRNA. However, the impact of these isoforms on downstream targets is less understood and may alter effective GRN levels. To test this hypothesis, we used NIH3T3 cells incubated with either of two isoforms of key developmental gene Fgf8: Fgf8a and Fgf8b. These variants have been shown to play different roles during the development of tissues such as the brain and have differing binding affinities to their receptor. However, their impact on downstream Fgf8 targets is less well known. I show that Fgf8b has a higher impact on the activation of the downstream signaling pathway pERK, target gene expression, and proliferation compared to Fgf8a. These results suggest that AS of Fgf8 can act as a mechanism of modifying gene dosage.

Environmental factors may also induce alterations to developmental GRNs. To test this, we treated developing chick limbs with perflurooctane sulfonate (PFOS), a toxic chemical found in a variety of consumer products. This resulted in limb malformations. We are currently evaluating impacts to gene expression. Additionally, PFOS treatment of Sertoli cells, critical germ line support cells, induced differential splicing of genes enriched in pathways associated with Sertoli cell function, including DNA damage response and repair.