Loss of Glycogen Synthase Kinase 3 Isoforms During Murine Oocyte Growth Induces Offspring Cardiac Dysfunction 1 Running title - Absence of oocyte GSK3 and neonatal death

Glycogen synthase kinase-3 (GSK3) is a constitutively active serine threonine kinase with i) two isoforms (GSK3A and GSK3B) having unique and overlapping functions, ii) multiple molecular intracellular mechanisms involving phosphorylation of diverse substrates, and iii) implications in pathogenesis of many diseases. Insulin causes phosphorylation and inactivation of GSK3 and mammalian oocytes have a functional insulin signaling pathway whereby prolonged elevated insulin during follicle/oocyte development causes GSK3 hyperphosphorylation, reduced GSK3 activity, and altered oocyte chromatin remodeling. Periconceptional diabetes and chronic hyperinsulinemia are associated with congenital malformations and onset of adult diseases of cardiovascular origin. Objectives were to produce transgenic mice with individual or concomitant loss of GSK3A and/or GSK3B and investigate the in vivo role of oocyte GSK3 on fertility, fetal development, and offspring health. Wild type males bred to females with individual or concomitant loss of oocyte GSK3 isoforms did not have reduced fertility. However, concomitant loss of GSK3A and GSK3B in the oocyte significantly increased neonatal death rate due to congestive heart failure secondary to ventricular hyperplasia. Individual loss of oocyte GSK3A or GSK3B did not induce this lethal phenotype. In conclusion, absence of oocyte GSK3 in the periconceptional period does not alter fertility yet causes offspring cardiac hyperplasia, cardiovascular defects, and significant neonatal death. These results support a developmental mechanism by which periconceptional hyperinsulinemia associated with maternal metabolic syndrome, obesity, and/or diabetes can act on the oocyte and impact offspring cardiovascular development, function, and congenital heart malformation. Summary: Absence of both glycogen synthase kinase 3 isoforms in the oocyte during late stages of oogenesis does not influence fertility but impairs fetal development and offspring survival.