Maureen Anne Gannon, PhD

Maureen Anne Gannon, PhD

Professor, Medicine

Professor, Cell and Developmental Biology

Professor, Molecular Physiology and Biophysics

7425C MRB IV
(615) 936-2676


Molecular genetics of pancreas development, organogenesis, morphogenesis, islet function, diabetes, transcription
factors

Research Description

The pancreas is essential for normal digestion and maintenance of blood sugar
levels. We study the role of genes and signaling pathways involved in the
development and function of specific cell types within the pancreas.

The HNF6 transcription factor is expressed in all pancreas cells early in
embryonic development, but is "turned off" in islet cells just before birth
in the mouse. We developed mice in which HNF6 is over-expressed or can be
inactivated conditionally. These studies reveal that HNF6 is essential to
generate the appropriate number of endocrine progenitor cells, but that it
must get "turned off" in order for the insulin-producing cells to function
properly. Current studies are examining how HNF6 interacts with other factors
in the embryonic pancreas to regulate endocrine differentiation. Our studies
also revealed that HNF6 is essential for normal growth and branching of the
pancreatic ductal epithelium. In the absence of HNF6, pancreatic duct
differentiation is impaired and the mice develop pancreatitis.

A second project in the lab examines the role of CTGF, a secreted factor
known to modulate growth factor signaling and affect cell proliferation and
migration in other organ systems. We found that loss of CTGF results in
decreased embryonic islet beta cell proliferation and defective islet
formation. We are using conditional gene inactivation and over-expression
strategies to determine how CTGF affects islet development and function
during embryogenesis and after transplantation.  In addition, we are
examining whether CTGF can enhance beta cell regeneration in adults after
significant beta cell destruction.

Finally, the FoxM1 transcription factor is highly expressed in proliferating
cells and is essential for normal cell division. We generated mice
specifically lacking FoxM1 in the pancreas. In these mice, the number of
insulin-producing cells fails to increase with body mass, resulting in
diabetes. Significantly, we found that FoxM1 is required downstream of all
proliferative stimuli in the insulin-producing beta cells. For example, the
number of beta cells expands via mitosis when animals are fed a high fat
diet, or during pregnancy. In FoxM1 mutants, this increase in mitosis does
not occur and the animals become diabetic. Our current studies are aimed at
characterizing the signaling pathways that activate FoxM1 expression and
activity as well as identifying target genes of FoxM1 in the
insulin-producing cells.