transcriptional control of β-cell genesis
The classical model of gene regulation relies upon sequence-specific interactions of nuclear proteins, called transcription factors, with the promoter regions of genes. The gene regulatory outcome of transcription factor binding to DNA is dependent on both the intrinsic properties of the factor and the regulatory or promoter context. Transcription factors have an indispensable role during all the stages of β-cell differentiation (Fig1). Our work has focused on a number of transcription factors important for β-cell development; the specific questions we asked in this research were:
What role does the Sry/HMG box factor Sox9 play during pancreas development?
We determined the expression pattern of Sox9 during pancreas development and demonstrated that it was involved in coordinating a network of factors that is both necessary for activation of the proendocrine transcription factor neurogenin 3 and for maintenance of a progenitor cell population.
What role does Mouse Atonal homolog 6 (Math6) play during endocrine cell development?
We determined that the basic helix-loop-helix transcription factor Math6 lies downstream of neurogenin 3, is activated by neurogenin 3, and is able to negatively regulate neurogenin 3; thus, Math6 could be important for regulating endocrine cell development. Genetic ablation of Math6 during development resulted in embryonic lethality prior to pancreas formation. We have generated a conditional null mouse to determine the function of Math6 specifically in the pancreas.