Dishevelled-associated activator of morphogenesis 1 (Daam1) is required for heart morphogenesis

Abstract

SUMMARYDishevelled-associated activator of morphogenesis 1 (Daam1), a member of the formin protein family, plays an important role in regulating the actin cytoskeleton via mediation of linear actin assembly. Previous functional studies of Daam1 in lower species suggest its essential role in Drosophila trachea formation and Xenopus gastrulation. However, its in vivo physiological function in mammalian systems is largely unknown. We have generated Daam1-deficient mice via gene-trap technology and found that Daam1 is highly expressed in developing murine organs, including the heart. Daam1-deficient mice exhibit embryonic and neonatal lethality and suffer multiple cardiac defects, including ventricular noncompaction, double outlet right ventricles and ventricular septal defects. In vivo genetic rescue experiments further confirm that the lethality of Daam1-deficient mice results from the inherent cardiac abnormalities. In-depth analyses have revealed that Daam1 is important for regulating filamentous actin assembly and organization, and consequently for cytoskeletal function in cardiomyocytes, which contributes to proper heart morphogenesis. Daam1 is also found to be important for proper cytoskeletal architecture and functionalities in embryonic fibroblasts. Biochemical analyses indicate that Daam1 does not regulate cytoskeletal organization through RhoA, Rac1 or Cdc42. Our study highlights a crucial role for Daam1 in regulating the actin cytoskeleton and tissue morphogenesis.

Systematic analysis of microRNA fingerprints in thrombocythemic platelets using integrated platforms

“…Recent data using Daam1-knockout mice have established a crucial role in heart morphogenesis by regulating filamentous actin assembly and cytoskeletal organization. 38 The associated embryonic lethality precluded detailed analysis of the hematopoietic system, although DAAM1's megakaryocyte-enriched pattern of expression presumably connotes functional properties relevant to megakaryocytopoiesis and/or proplatelet formation.…”

Formins at a glance

“…Formins also have essential roles in physiological processes ranging from cell motility in the immune system (Yayoshi-Yamamoto et al, 2000;Eisenmann et al, 2007;Shi et al, 2009), to gastrulation and neural tube closure (Habas et al, 2001;Sato et al, 2006;Lai et al, 2008), heart morphogenesis (Iskratsch et al, 2010;Li et al, 2011), kidney morphogenesis (Brown et al, 2010;Boyer et al, 2011a;Boyer et al, 2011b), and dendritic spine formation in neurons. Some of these functions depend on the actin nucleation and elongation activities of formins (Bartolini et al, 2008;Andrés-Delgado et al, 2010;Madrid et al, 2010;Andrés-Delgado et al, 2012;Ramabhadran et al, 2012;Stastna et al, 2012), which have been demonstrated by investigating point mutations that impair in these activities Lu et al, 2007;Ramabhadran et al, 2012).…”

Lack of Plakoglobin in Epidermis Leads to Keratoderma

“…BrdU Staining and Terminal Deoxynucleotidyltransferasemediated dUTP Nick End Labeling (TUNEL) Assay-BrdU and TUNEL assays were performed as described previously (9). Briefly, mice were intraperitoneally injected with BrdU labeling reagent (30 mg/kg of body weight) and killed 3-4 h later.…”

“…Transmission Electron Microscopy-Transmission electron microscopy was performed as described previously (9). Skin samples were fixed in modified Karnovsky's fixative (2% paraformaldehyde and 2% glutaraldehyde in 0.1 M phosphate buffer) at 4°C overnight.…”