Regulation and function of the Tyrosine Hydroxylase-insulin locus in cardiac and endocrine pancreas development

Figure 1

 

 

Figure 2

 

Insulin, in its precursor form proinsulin, is expressed from early stages of development, prior to pancreatic development. Our group has characterized proinsulin  effects as growth factor. We have demonstrated that proinsulin has an inductive role in cardiogenesis in the prepancratic chick embryo  (Figure 1) , and that it plays an antiapoptotic function in the retina (see retina project). These new functions, different from the classic hormonal role, appear in parallel to new mechanisms of gene regulation. We have found proinsulin embryonic transcripts, longer than the pancreatic, which have diminished translational activity, with respect to the canonical transcript. We have characterized that the dynamic expression of the different proinsulin transcripts in the precardiogenic area reflects a strict control of proinsulin levels, since its overexpression causes cardiac malformations.

We have also characterized the expression of TH in cardiac mesoderm and in the auricular region later, in embryonic stages prior to innervation. We have demonstrated that, possibly through dopamine, catecholamines participate in the formation and regionalization of the cardiac chambers, with an effect opposite to that of proinsulin (Figure 1).
A novel function of TH/catecholamines in pancreas development is under study now. The cell subpopulation that expresses TH in the mouse embryonic pancreas coincides with a group of endocrine cells which express glucagon (Figure 2). The presence of TH in these development phases appears to be required for the insulin secreting  cell precursors achieving normal differentiation (Figure 2).
 

Martínez-Campos E / Hernández-San Miguel E, López-Sánchez C, de Pablo F, Hernández-Sánchez C [2013] Alternative splicing variants of proinsulin mRNA and the effects of excess proinsulin on cardiac morphogenesis. FEBS Letters 587: 2272-2277.

 

López-Sánchez C, Bártulos O, Martínez-Campos E, Gañán C, Valenciano AI, García-Martínez V, De Pablo F, Hernández-Sánchez C [2010] Tyrosine hydroxylase is expressed during early heart development and is required for cardiac chamber formation. Cardiovasc Res 88:111-120. Editorial Comment: Thomas Brandt. Exciting news: Catecholamines in induction and regionalization of the heart.

 

Hernández-Sánchez C, Mansilla A, de Pablo F, Zardoya R [2008] Evolution of the insulin receptor. Mol Biol Evol 25:1043-1053

 

 

Coordinator: Catalina Hernández-Sánchez

 

Participants: Patricia Vázquez, Ana Mª Robles, Cayetana Murillo and Flora de Pablo