Requirement for AP-2α in cardiac outflow tract morphogenesis

Abstract

Most developing structures that express the transcription factor gene AP-2alpha are compromised in AP-2alpha mutant mouse embryos. Since the cardiac neural crest population is one prominent site of AP-2alpha expression, and because the neural crest is known to be required for normal cardiac morphogenesis, we have investigated the involvement of AP-2alpha in cardiac development. All AP-2alpha-deficient embryos examined had malformations of the outflow tract of the developing heart: most had double outlet right ventricle, and a small fraction had persistent truncus arteriosus. To visualize AP-2alpha-expressing cells during the period of cardiac morphogenesis, we established a new mutant germline allele in which an IRES-lacZ sequence was inserted by homologous recombination into the AP-2alpha locus. Positive expression was observed in the cardiac neural crest population during the E9.5-10.5 period (as well as in other known domains of AP-2alpha expression previously noted by in situ hybridization studies), and was mostly extinguished by E11.5 when the cardiac neural crest has migrated into the outflow tract of the developing heart. Importantly, the distribution of AP-2alpha-expressing cardiac neural crest appeared to be identical in normal and mutant embryos. From this analysis, we propose that the AP-2alpha gene functions within the neural crest lineage, that AP-2alpha is not required for neural crest cell migration, and that normal AP-2alpha gene function is required prior to E11.5. AP-2alpha may be involved in an interaction between neural crest and surrounding tissues in the subpharyngeal region, thereby promoting normal outflow tract morphogenesis.

Gene Targeting Reveals a Widespread Role for the High-Mobility-Group Transcription Factor Sox11 in Tissue Remodeling

“…All mice analyzed exhibited a ventricular septation defect that was closely associated with outflow tract malformations that ranged from common arterial trunk to double outlet right ventricle. Similar heart phenotypes have been observed in many different knockout mice and have been found to be incompatible with postnatal life (1,5,13,23,34).…”

Neural crest migration is driven by a few trailblazer cells with a unique molecular signature narrowly confined to the invasive front

“…7). TFAP2A has previously been shown to be expressed by premigratory and migratory cranial NC cells and be important in NC induction, proliferation and differentiation in mice, zebrafish and Xenopus, as well as avian facial tissue growth (Mitchell et al, 1991;Chazaud et al, 1996;Schorle et al, 1996;Shen et al, 1997;Pfisterer et al, 2002;Brewer et al, 2002;Luo et al, 2003;Knight et al, 2003Knight et al, , 2004Barrallo-Gimeno et al, 2004;Li and Cornell, 2007;Wang et al, 2011). We have previously shown that when leaders are prevented from migrating into the target site by a physical barrier, trailing NC cells sense the paused leaders, reroute around the barrier and become the new leaders (Kulesa et al, 2005).…”

Cell autonomous roles for AP‐2α in lens vesicle separation and maintenance of the lens epithelial cell phenotype

“…To generate a conditional knockout of AP-2␣ in the lens placode, mice heterozygous for the Tcfap2a:LacZ KI allele (maintained on an outbred Black Swiss genetic background), a null allele (Brewer et al, 2002), were bred with heterozygous Le-Cre mice (maintained on an FVB/N genetic background) that expressed Cre-recombinase specifically in cells within the early lens placode (Ashery-Padan et al, 2000). Resultant progeny from this cross, heterozygous for both the Cre transgene and the Tcfap2a:LacZ KI allele, were then bred with mice homozygous for the Alflox allele (maintained on a mixed 129/ Black Swiss background), an allele of Tcfap2a in which paired loxP sites flank a region encoding a critical region of the DNA binding domain (Brewer et al, 2004).…”