The Foxa family of forkhead transcription factors—Foxa1, Foxa2, and Foxa3—play evolutionarily conserved and important roles in endodermal organ formation and function. Besides these developmental roles, Foxa transcription factors regulate glucose metabolism, homeostasis in adipocytes, longevity, and apoptosis in different organisms. More recently, Foxa transcription factors have come back into the spotlight with essential roles in the development of midbrain dopaminergic neurons. Loss of midbrain dopaminergic neurons of the substantia nigra (SN) subgroup is the hallmark of Parkinson disease.

We recently demonstrated that Foxa1 and Foxa2 have multiple and essential roles in the development of midbrain dopaminergic neurons in mice (1). Our data from phenotypic analyses of single and double Foxa1 and Foxa2 mutant embryos demonstrate that these genes function in a dose-dependent manner to regulate specification and differentiation of midbrain DA progenitors. Interestingly, results in this paper by Kittappa et al. suggest another role for Foxa2 in regulating survival of adult...  Read more

The Foxa family of forkhead transcription factors—Foxa1, Foxa2, and Foxa3—play evolutionarily conserved and important roles in endodermal organ formation and function. Besides these developmental roles, Foxa transcription factors regulate glucose metabolism, homeostasis in adipocytes, longevity, and apoptosis in different organisms. More recently, Foxa transcription factors have come back into the spotlight with essential roles in the development of midbrain dopaminergic neurons. Loss of midbrain dopaminergic neurons of the substantia nigra (SN) subgroup is the hallmark of Parkinson disease.

We recently demonstrated that Foxa1 and Foxa2 have multiple and essential roles in the development of midbrain dopaminergic neurons in mice (1). Our data from phenotypic analyses of single and double Foxa1 and Foxa2 mutant embryos demonstrate that these genes function in a dose-dependent manner to regulate specification and differentiation of midbrain DA progenitors. Interestingly, results in this paper by Kittappa et al. suggest another role for Foxa2 in regulating survival of adult midbrain dopaminergic neurons. However, it remains to be determined whether and how Foxa2 functions cell- autonomously to regulate survival specifically of SN dopaminergic neurons.

Despite these unresolved issues, these two papers together demonstrate convincingly that Foxa1 and Foxa2 transcription factors are key determinants of dopaminergic neuron specification and differentiation in the midbrain and may facilitate the generation of dopaminergic neurons from human embryonic stem cells.

References:
Ferri AL, Lin W, Mavromatakis YE, Wang JC, Sasaki H, Whitsett JA, Ang SL. Foxa1 and Foxa2 regulate multiple phases of midbrain dopaminergic neuron development in a dosage-dependent manner. Development. 2007 Aug 1;134(15):2761-9. Abstract

Kittappa R, Chang WW, Awatramani RB, McKay RD. The Foxa2 gene controls the birth and spontaneous degeneration of dopamine neurons in old age. 2007 Dec 11; PLoS Biology 5(12);e325. Abstract

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