Project Summary
The endocrine pancreas is responsible for the production of several hormones, including insulin, important in the
regulation of carbohydrate metabolism and glucose homeostasis. Both the development of the endocrine pancreas and
its proper function within the context of the mature organ rely on networks of transcription factors that are not yet well
understood. Among these, the Krüppel-like protein, Gli-similar 3 (Glis3) has been found to be important in the
development of insulin-producing ß cells and is essential for insulin transcription in adults. Currently, little is known about
the specific roles Glis3 plays in pancreatic cell fate specification or its involvement in the postnatal expansion of ß cell
mass.
In this proposal, experiments are described intended to characterize pancreatic development and function in the
glis3sa17645 mutant zebrafish line. Zebrafish homozygous for the glis3sa17645 allele (glis3-/-) ubiquitously lack glis3
expression. In Specific Aim 1, we will characterize pancreatic development in glis3 knockout fish to determine whether
glis3 is required for the formation of endocrine progenitor cells or their subsequent specification to islet fates. Emphasis
will be placed on identifying the mechanisms that regulate islet maturation and mass expansion. The experiments
described in Specific Aim 2 are designed to examine the role of glis3 in the expansion of ß cell mass in adults responding
to nutrient excess. Finally, in Specific Aim 3, ß cell regeneration will be studied in glis3 mutant zebrafish following
chemical ablation.
The research described in this proposal will be conducted at a regional comprehensive university that serves a
predominately rural, economically underdeveloped community for whom access to scientific research is traditionally
restricted. The research will be completed with extensive support from undergraduate researchers who will gain the
opportunity to co-author manuscripts and present findings at local, state, and national meetings.
Broadly, the completion of the studies outlined in this proposal will increase our understanding of how Glis3 specifies
endocrine fates in the pancreas and may help shed light on how Glis3 mutations lead to diseases in humans including
diabetes mellitus. Furthermore, a greater understanding of the mechanisms that regulate pancreatic development is likely
to be achieved including a more thorough knowledge of the transcription factor networks that regulate ß cell mass
expansion and regeneration in zebrafish. Ultimately, completion of the research described may lead to the establishment
of a complementary zebrafish model for the study of diabetes or other Glis3-related diseases.
