These Creface transgenic mice express Cre recombinase under the control of the human transcription factor AP-2, alpha (Tfap2a) promoter/enhancer elements. A polyadenylation sequence followed by parts of exons 5-6 of Tfap2a, encoding the frontonasal prominence (FNP) and limb enhancer elements, was inserted downstream of the cre sequence. AP-2alpha is a transcription factor expressed in the neural tube, and in cranial and cardiac neural crest cells in the developing embryo, as well as in the progress zone of the limb bud, the developing kidney, the eye, and surface ectoderm. The transgene was found to have integrated into intron 9 of the hedgehog acyltransferase (Hhat) gene, abolishing Hhat gene function. HHAT deficiency has been associated with holoprosencephaly, failure of the forebrain to bifurcate, together with acrania and agnathia. Hemizygous mice are viable and fertile, while homozygotes are embryonic lethal. These mutants lack Hhat activity resulting in craniofacial development defects evident between E14.5 and E17.5. Homozygous embryos exhibit abnormal morphology of the frontonasal, mandibular, and maxillary processes. They also exhibit defects in the development of the cranium, eye, nasal cavity and septum, mouth, and palates. Neural crest morphology is also altered, as is midbrain and forebrain morphology. Expression of cre recombinase was detected in the embryonic face and limb mesenchyme. When crossed with a strain containing a loxP site-flanked sequence, Cre-mediated recombination results in deletion of the flanked sequence in cre-expressing cells.
For example, when bred to STOCK Tfap2atm2Will/J mice (Stock No. 023406) expressing a floxed-Tfap2a gene, frontonasal knockout (FKO) mice exhibit midfacial growth anomalies including shortened snouts and wide-set eyes by postnatal day 15.
