PAX3, NEURAL CREST AND CARDIOVASCULAR DEVELOPMENT

The understanding of cardiovascular development has begun a transforma tion from the descriptive science of anatomy and embryology to a molec ular understanding of the cellular and subcellular events leading to p roper cardiac morphogenesis. Powerful fools available to molecular gen eticists have identified numerous examples of specific gene defects th at result in predictable cardiovascular abnormalities. Not only have c ertain genes been ''knocked out'' (mutated by homologous recombination in embryonic stem cells), but also single gene defects have been foun d to underlie the cardiovascular derangements observed in certain inbr ed mouse lines. Such is the case for the mouse mutant Splotch, which w as first described in 1954 as a spontaneously occurring mutation resul ting in a white belly spot. More recently the genetic defect of all of the various Splotch alleles has been found to be due to mutations or deletions of a gene called Pax-3. In the homozygous state, these mutat ions result in embryonic lethality at about day 13.5 of mouse embryoge nesis (E13.5). These embryos display abnormalities strikingly reminisc ent of human DiGeorge syndrome. These include outflow tract abnormalit ies of the heart, such as double-outlet right ventricle (DORV) and per sistent truncus arteriosus (PTA), as well as abnormalities of the grea t vessels and the thyroid and parathyroid glands. These defects sugges t an underlying abnormality of neural crest, including its contributio n to the cardiovascular system. (C) 1996, Elsevier Science Inc.