Role of the forkhead transcription factor Foxa2 in the development of the ventral mesencephalon : a study using conditional mouse mutants
The developing mesencephalon consists of two distinct domains. The dorsal domain, the tectum, gives rise to the superior and inferior colliculi, which in the adult receives information from the optic and auditory systems respectively. The ventral domain gives rise primarily to 3 distinct nuclei which are involved in the control of motor movement, such as the mesencephalic dopaminergic neurons, which are the neurons affected in Parkinson's disease, the oculomotor complex and the red nucleus. Forkhead transcription factors of the A subgroup, Foxa1 and Foxa2, are expressed in the ventral midbrain, in addition to being expressed in the notochord, floorplate and gut during embryonic development. In this study, I focused on the role of Foxal, a member of the forkheadVwinghelix family of transcription factors in the specification of the ventral mesencephalic neurons. To address the role of Foxa1 specifically in the mesencephalon, we have generated a conditional allele of Foxa2, referred to as Foxa2ox and crossed this mouse line with Wntl-Cre transgenic animals. Inactivation of Foxa2 protein in mesencephalic progenitors of Wntl-Cre Foxa'f0 embryos occurred by E8.5. Severe reduction in the numbers of Islet 1* oculomotor, Brn3a+ red nucleus and tyrosine hydroxylase* dopaminergic neurons were observed in Foxa2 conditional mutant embryos at El2.5, which were preceded by changes in the expression of the morphogen Shh as well as Foxal and Nkx transcription factors. Detailed phenotypic characterization by histology, RNA in-situ hybridization and immunohistochemistry has revealed novel roles for Foxa2 in regulating the patterning of mesencephalic progenitors as well as their differentiation. In collaboration with another postdoctoral fellow in the laboratory, we have also shown that Foxal plays a very similar role and can compensate for the function of Foxa2 in the ventral mesencephalon.