Severe head dysgenesis resulting from imbalance between anterior and posterior ontogenetic programs

Head dysgenesis is a major cause of fetal demise and craniofacial malformation. Although mutations in genes of the
head ontogenetic program have been reported, many cases remain unexplained. Head dysgenesis has also been
related to trisomy or amplification of the chromosomal region overlapping the CDX2 homeobox gene, a master
element of the trunk ontogenetic program. Hence, we investigated the repercussion on head morphogenesis of the
imbalance between the head and trunk ontogenetic programs, by means of ectopic rostral expression of CDX2 at
gastrulation. This caused severe malformations affecting the forebrain and optic structures, and also the frontonasal
process associated with defects in neural crest cells colonization. These malformations are the result of the
downregulation of genes of the head program together with the abnormal induction of trunk program genes.
Together, these data indicate that the imbalance between the anterior and posterior ontogenetic programs in
embryos is a new possible cause of head dysgenesis during human development, linked to defects in setting up
anterior neuroectodermal structures.