The foxa2 Gene Controls the Birth and Spontaneous Degeneration of Dopamine Neurons in Old Age

Abstract

Parkinson disease affects more than 1% of the population over 60 y old. The dominant models for Parkinson disease are based on the use of chemical toxins to kill dopamine neurons, but do not address the risk factors that normally increase with age. Forkhead transcription factors are critical regulators of survival and longevity. The forkhead transcription factor, foxa2, is specifically expressed in adult dopamine neurons and their precursors in the medial floor plate. Gain- and loss-of-function experiments show this gene, foxa2, is required to generate dopamine neurons during fetal development and from embryonic stem cells. Mice carrying only one copy of the foxa2 gene show abnormalities in motor behavior in old age and an associated progressive loss of dopamine neurons. Manipulating forkhead function may regulate both the birth of dopamine neurons and their spontaneous death, two major goals of regenerative medicine.

Author Summary

The restoration of dopamine neurons is a major focus of stem cell biology and regenerative medicine. The gradual loss of these neurons is a hallmark of Parkinson disease. Dopamine neurons in the midbrain convey important sensory and motor functions to the forebrain. We show that the transcription factor FOXA2 plays a central role in the birth and death of dopamine neurons in the midbrain. By defining their precursors in the ventral midbrain, we show that dopamine neurons are derived from organizer cells in the floor plate (the ventral cells of the neural tube, the embryonic foundation of the central nervous system). We also show that FOXA2 specifies the floor plate and induces the birth of dopamine neurons. Mice with only a single copy of the foxa2 gene acquire motor deficits and a late-onset degeneration of dopamine neurons. This spontaneous cell death preferentially affects neurons associated with Parkinson disease. This work provides new strategies to generate neurons in the laboratory and to block their death in old age.

Abstract

The connection between development and neurodegeneration is emphasized via a new mouse knockout of a transcription factor that is critical for dopamine neuron specification, which produces a late-onset, asymmetric degenerative condition in a manner very similar to human Parkinson disease.