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

Raja Kittappa,Rajeshwar B Awatramani,Wendy W Chang,Ronald D G Mckay,Huda Y Zoghbi

doi:10.1371/journal.pbio.0050325

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.

Highlights

Midbrain dopamine neurons play important roles in motor control, reward, addiction, attention, and cognition [1,2]
Foxa2 expression is restricted to the floor plate, a specialized ventral region that regulates the differentiation of nearby neurons by secreting the morphogenic signal sonic hedgehog (SHH) [14,15]
The restoration of dopamine neurons is a major focus of stem cell biology and regenerative medicine

Summary

Introduction

Midbrain dopamine neurons play important roles in motor control, reward, addiction, attention, and cognition [1,2]. A progressive loss of dopamine neurons is a defining feature of Parkinson disease. To improve access to these neurons, techniques have been developed to derive them from precursors dissected from the fetal midbrain and from pluripotent embryonic stem (ES) cell lines [5,6,7,8,9,10,11]. Despite this effort, our knowledge of the mechanisms controlling the birth and death of these cells is still limited

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