Disease relevance of tfap2a

• We show that mutations at the zebrafish locus previously called mont blanc (mob) or lockjaw (low) encode tfap2a [1].

High impact information on tfap2a

• The expression of the noradrenergic marker genes th and dbh is strongly reduced, as well as the transcription factors gata2 and tfap2a (Ap-2alpha) [2].
• Zebrafish embryos deficient for both tfap2a and tfap2b show defects in epidermal cell survival and lack NCC-derived cartilages [3].
• Furthermore, surviving neural crest cells in tfap2a/mob(m610) mutant embryos proliferate normally and later differentiate to individual derivatives [4].
• Using a positional candidate cloning approach we identified an A to G transition within the 3' splice site of the sixth intron of the tfap2a gene that abolishes the last exon encoding the crucial protein dimerization and DNA-binding domains [4].
• TUNEL assay and Acridine Orange staining revealed that in the absence of tfap2a a subset of neural crest cells are unable to undergo terminal differentiation and die by apoptosis [4].

Biological context of tfap2a

• Consistent with this, injection of antisense morpholino oligonucleotides directed against splice sites in tfap2a into wild-type embryos produces a phenotype identical to low [5].
• A point mutation in low truncates the DNA binding and dimerization domains of tfap2a, causing a loss of function [5].
• Thus, tfap2a does not appear to be involved in early specification and cell proliferation of neural crest, but it is a key regulator of an early differentiation phase and is required for cell survival in neural crest derived cell lineages [4].
• In mob(m610) mutant embryos, the cell number of neuronal and glial derivatives of neural crest is greatly reduced, suggesting that tfap2a is required for their normal development [4].
• In addition, in tfap2a/tfap2c doubly deficient embryos cranial placode derivatives are reduced, although gene expression characteristic of pre-placodal domain is normal [6].

Anatomical context of tfap2a

• Noradrenergic neurons in the zebrafish hindbrain are induced by retinoic acid and require tfap2a for expression of the neurotransmitter phenotype [1].
• For the posterior hindbrain, we identify retinoic acid as an important signal to induce NA differentiation in the medulla oblongata and area postrema, where it expands the tfap2a expression domain and thus acts upstream of tfap2a [1].
• The mutant phenotype reveals that tfap2a is essential for the development of hindbrain noradrenergic (NA) neurons of the locus coeruleus, medulla and area postrema, as well as for sympathetic NA neurons, epibranchial placode derived visceral sensory ganglia, and craniofacial and trunk crest derivatives [1].
• Here, we show essential functions for zebrafish tfap2a and tfap2b in development of the facial ectoderm, and for signals from this epithelium that induce skeletogenesis in neural crest cells (NCCs) [3].

References