WNT5A mutations in patients with autosomal dominant Robinow syndrome.

Robinow syndrome is a skeletal dysplasia with both autosomal dominant and autosomal recessive inheritance patterns. It is characterized by short stature, limb shortening, genital hypoplasia, and craniofacial abnormalities. The etiology of dominant Robinow syndrome is unknown; however, the phenotypically more severe autosomal recessive form of Robinow syndrome has been associated with mutations in the orphan tyrosine kinase receptor, ROR2, which has recently been identified as a putative WNT5A receptor. Here, we show that two different missense mutations in WNT5A, which result in amino acid substitutions of highly conserved cysteines, are associated with autosomal dominant Robinow syndrome. One mutation has been found in all living affected members of the original family described by Meinhard Robinow and another in a second unrelated patient. These missense mutations result in decreased WNT5A activity in functional assays of zebrafish and Xenopus development. This work suggests that a WNT5A/ROR2 signal transduction pathway is important in human craniofacial and skeletal development and that proper formation and growth of these structures is sensitive to variations in WNT5A function.

Wnt5a is required for cardiac outflow tract septation in mice.

Lack of septation of the cardiac outflow tract (OFT) results in persistent truncus arteriosus (PTA), a form of congenital heart disease. The outflow myocardium expands through addition of cells originating from the pharyngeal mesoderm referred to as secondary/anterior heart field, whereas cardiac neural crest (CNC) cell-derived mesenchyme condenses to form an aortopulmonary septum. We show for the first time that a mutation in Wnt5a in mice leads to PTA. We provide evidence that Wnt5a is expressed in the pharyngeal mesoderm adjacent to CNC cells in both mouse and chicken embryos and in the myocardial cell layer of the conotruncus at the time when CNC cells begin to form the aortopulmonary septum in mice. Although expression domains of secondary heart field markers are not altered in Wnt5a mutant embryos, the expression of CNC cell marker PlexinA2 is significantly reduced. Stimulation of CNC cells with Wnt5a protein elicits Ca2+ transients, suggesting that CNC cells are capable of responding to Wnt5a. We propose a novel model in which Wnt5a produced in the OFT by cells originating from the pharyngeal mesoderm signals to adjacent CNC cells during formation of the aortopulmonary septum through a noncanonical pathway via localized intracellular increases in Ca2+.

PINCH-1 expression during early avian embryogenesis: implications for neural crest and heart development.

The invasion of the cardiac neural crest (CNC) into the outflow tract (OFT) and subsequent OFT septation are critical events during vertebrate heart development. We previously had performed four modified differential display (DD) screens in the chick embryo to identify genes that may be involved in CNC and heart development. Full-length sequence of one of the DD clones has been obtained and identified as chick PINCH-1. This particularly interesting new cysteine-histidine-rich protein contains five protein-binding LIM domains (five double zinc fingers), a nuclear localization signal, and a nuclear export signal, allowing it to participate in integrin and growth factor signaling and possibly act as a transcription factor. We show here for the first time that chick PINCH-1 is expressed in neural crest cells, both in the neural fold and cardiac OFT, and is also expressed in mesoderm derived-structures, including the myocardium, during avian embryogenesis. The normal expression pattern and overexpression in neural crest cell explants suggest that PINCH-1 may be a regulator of neural crest cell adhesion and migration.

Addressing the maintenance of certification challenge: the College of American Pathologists response.

CONTEXT: The American Board of Medical Specialties Maintenance of Certification (MOC) process will become effective in 2006. The College of American Pathologists (CAP) Education Committee defined pathology-specific competencies within MOC categories and used data from a survey of pathologists to create education courses targeted to each MOC category. OBJECTIVE: To define pathology-specific competencies within MOC categories and to identify priority learning needs for pathologists. DESIGN: A 5-step process was completed for defining pathology-specific competencies within MOC categories and creating education courses targeted to competencies identified in each MOC category. A random survey was distributed to identify priority learning needs based on the gap between the importance rating of each knowledge and skill statement and a rating of current level of proficiency in 3 areas. RESULTS: Specific competencies and knowledge and skill statements were identified for each MOC competency category. Findings indicate pathologists believe they are poorly prepared for practice in competency categories related to systems-based practice and practice-based learning and improvement. CONCLUSIONS: The CAP has focused education efforts on identifying a process for defining and responding to the MOC challenge. Pathologists have told us that they have significant needs for learning in specified areas and the CAP will focus development of education courses to meet those identified needs.