Parkinson disease is caused by the degeneration of dopaminergic (DA) neurons in the midbrain. To treat this illness, many laboratories are looking for ways to prevent neuron loss or support the survival of remaining DA neurons at early stages. DA neurons in chick embryos require transforming growth factor-β (TGFβ), but it has not been clear when TGFβ acts in DA neuron development or how exactly it signals in this system. In general, TGFβ signaling activates transcription factor complexes consisting of Smads and other cofactors.

Zhang et al. in this issue (pp 77–86) report that the Smad-associated cofactor HIPK2 is expressed in the developing midbrain. HIPK2-null mice showed peri- and postnatal loss of about 40% of DA neurons in the substantia nigra, even though the DA neurons were initially generated in normal numbers. The figure shows embryonic day 12.5 midbrain from HIPK2−/− embryos in coronal section, stained for Ngn2 in red (to label progenitors) and tyrosine hydroxylase in green (labeling mature DA neurons). The tissue looks completely normal at this stage. These results support the idea that DA neurons, like several other neuron populations, are generated in excess, and their numbers are later adjusted by competition for limited amounts of survival factors such as TGFβ.

The HIPK2-null mice showed Parkinson-like motor symptoms and may be useful as a new disease model. It remains to be seen, however, whether TGFβ-Smad-HIPK2 signaling can rescue DA neurons late in life, when Parkinson disease typically manifests.