DAAM1 and DAAM2 are co-required for myocardial maturation and sarcomere assembly.

摘要: Wnt ligands regulate heart morphogenesis but the underlying mechanisms remain unclear. Two Formin-related proteins, DAAM1 and 2, were previously found to bind effector Disheveled. Here, since 2 nucleate actin mediate Wnt-induced cytoskeletal changes, a floxed-allele of Daam1 was used disrupt its function specifically in myocardium investigate Wnt-associated pathways. Homozygous conditional knockout (CKO) mice viable had misshapen hearts poor cardiac function. The defects CKO observed by mid-gestation associated with loss protrusions from cardiomyocytes invading outflow tract. Further, these exhibited noncompaction cardiomyopathy (NCM) deranged cardiomyocyte polarity. Interestingly, that also homozygous for an insertion disrupting Daam2 (DKO) stronger NCM, severely reduced function, disrupted sarcomere structure, increased myocardial proliferation, suggesting DAAM2 have redundant functions. While RhoA unaffected Daam1/2 DKO mice, AKT activity lower than controls, raising issue whether DAAM1/2 are only mediating signaling. Daam1-floxed thus bred Wnt5a null identify genetic interactions. heterozygous allele NCM more severe consistent acting common pathway. However, deleting further homozygous-null hearts, has Wnt5a-independent roles development.