Molecular Cell Differentiation
Studying the molecular mechanisms controlling cell destiny and diversity is of fundamental interest for understanding pathological processes and diseases. We are using mouse genetics to study the role of transcription factors during cell differentiation in the endocrine pancreas and in the ventral midbrain. In the pancreas, we are interested in molecules that control the endocrine cell subtype specification. In addition, we are studying animal models to uncover molecular pathways promoting beta-cell regeneration in the adult pancreas. In the midbrain the specification of dopaminergic neurons is under the control of several transcription and secreted factors. Specifically, we want to identify factors that interact with Lmx1 a/b in order to promote the generation of functionally distinct dopaminergic neuron populations. Moreover, we have established induced pluripotent cells (iPS) from four Parkinson patients. These cells were used to generate neuronal precursor cells, as well as dopaminergic neurons that will serve to identify possible molecular alterations related to Parkinson's disease.
During the specification of the different hormone producing cells of the endocrine pancreas (insulin, glucagon, somatostatin, pancreatic polypeptide, and ghrelin) two factors, Pax4 and Arx, were found to undergo reciprocal inhibitory interaction to endow endocrine progenitors with a beta-/delta-cell fate or alpha-cell destiny, respectively. Accordingly, Pax4 is required for the formation of insulin producing cells, while Arx is necessary for the generation of alpha-cells. Our results clearly established Pax4 and Arx as major players during the specification of endocrine cell subtypes. Interestingly, the forced expression of Pax4 in alpha-cells was able to convert these into cells with beta-cell characteristics. Moreover, transgenic mice misexpressing Pax4 are able to counter chemically induced diabetes. It appears that upon injury the endocrine pancreas has some capacity to regenerate. However, in which part of the pancreas "stem cells" may reside is a matter of a controversial debate. Therefore, novel animal models for diabetes are needed to uncover the apparent intrinsic capacity of the endocrine pancreas to undergo regeneration and to provide new insights into their molecular mechanism.