Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus.

Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.

Toward an understanding of the genetics of murine cardiac pacemaking and conduction system development.

We distinguish the cardiac pacemaking and conduction system (CPCS) from neighboring working cardiomyocytes by its function to generate and deliver electrical impulses within the heart. Yet the CPCS is a series of integrated but distinct components. The components must act in a coordinated fashion, but they are also functionally, molecularly, and electrophysiologically unique. Understanding the differentiation and function of this elegant and complex system is an exciting challenge. Knowledge of genes and signaling pathways that direct CPCS development is at present minimal, but the use of transgenic mice represents an enormous opportunity for elucidating the unknown. Transgenic marker lines have enabled us to image and manipulate the CPCS in new ways. These tools are now being used to examine the CPCS in mutants where its formation and function is altered, generating new information and directions for study of the genetics of CPCS development.

Molecular and functional maturation of the murine cardiac conduction system.

The rhythmic heartbeat reflects a highly coordinated electrical wave, initiated and propagated throughout the myocardium by the specialized cardiac conduction system (CCS). Conduction system abnormalities affect millions of individuals, with symptoms from merely bothersome palpitations to fainting or even sudden death. Despite years of investigation, knowledge of the genes and molecules that direct CCS development and function are incomplete. In 1977, Viragh and Challice published the first in a series of articles describing the morphologic development of the murine CCS. The framework established by those reports now can be revisited in light of recent data. Imaging the developing CCS-using genetically engineered mice combined with functional assays, including optical mapping of cardiac electrical excitation-reveal some of the earliest events in CCS formation and function. These findings build on the experiments of Viragh and Challice, leading to a more integrated picture of conduction system development in the mammalian embryo.

Convergence and extension in vertebrate gastrulae: cell movements according to or in search of identity?

During vertebrate gastrulation, convergence and extension cell movements both narrow and lengthen the forming embryonic axis. Concurrently, positional information established principally by the ventral-to-dorsal gradient of bone morphogenetic protein activity specifies cell fates within the gastrula. New data, primarily from zebrafish, have identified domains of distinct convergence and extension movements, and have established a role for the noncanonical Wnt signaling pathway in promoting the mediolateral cell polarization that underlies this morphogenetic process. Other observations suggest the intriguing possibility that positional information regulates convergence and extension movements in parallel with cell-fate specification.

Bmp activity gradient regulates convergent extension during zebrafish gastrulation.

During vertebrate gastrulation, a ventral to dorsal gradient of bone morphogenetic protein (Bmp) activity establishes cell fates. Concomitantly, convergent extension movements narrow germ layers mediolaterally while lengthening them anteroposteriorly. Here, by measuring movements of cell populations in vivo, we reveal the presence of three domains of convergent extension movements in zebrafish gastrula. Ventrally, convergence and extension movements are absent. Lateral cell populations converge and extend at increasing speed until they reach the dorsal domain where convergence speed slows but extension remains strong. Using dorsalized and ventralized mutants, we demonstrate that these domains are specified by the Bmp activity gradient. In vivo cell morphology and behavior analyses indicated that low levels of Bmp activity might promote extension with little convergence by allowing mediolateral cell elongation and dorsally biased intercalation. Further, single cell movement analyses revealed that the high ventral levels of Bmp activity promote epibolic migration of cells into the tailbud, increasing tail formation at the expense of head and trunk. We show that high Bmp activity limits convergence and extension by negatively regulating expression of the wnt11 (silberblick) and wnt5a (pipetail) genes, which are required for convergent extension but not cell fate specification. Therefore, during vertebrate gastrulation, a single gradient of Bmp activity, which specifies cell fates, also regulates the morphogenetic process of convergent extension.