December 12, 2013

VU study points to central regulator of neuron development

Developmental biologist Chin Chiang, Ph.D., and his colleagues have discovered that Purkinje neurons in the cerebellum act as central regulators of neuronal development.

Chin Chiang, Ph.D., right, Jonathan Fleming and colleagues are studying neurons that act as central regulators of neuronal development in the cerebellum. (photo by Joe Howell)

The cerebellum — the “little brain” at the base of the brain — plays important roles in motor control, and has recently been implicated in cognition and social behavior.

Its small size and relatively simple architecture make the cerebellum an attractive brain region for studying nervous system development, said Chin Chiang, Ph.D., professor of Cell and Developmental Biology.

Chiang and his colleagues reported last month in Developmental Cell that Purkinje neurons — prominent cerebellar neurons that send signals to the rest of the brain — act as central regulators of neuronal development in the cerebellum.

Led by graduate student Jonathan Fleming, the investigators showed that the signaling molecule Sonic hedgehog, which is produced by Purkinje neurons, promotes the proliferation of two different types of precursor neurons that will ultimately become either excitatory or inhibitory interneurons.

“[rquote]It was very surprising that the Purkinje cell can simultaneously regulate the production of these two completely different neuronal cell types[/rquote],” Chiang said. “These cells are not only functionally different, but they are located in different positions in the cerebellum as well.”

Interestingly, he noted, both types of mature interneurons ultimately project to and regulate the Purkinje neurons themselves.

“It seems that the Purkinje cells have a role in balancing their own excitatory and inhibitory inputs, by regulating the production of these interneurons,” Chiang said.

The findings could be a model for the development of similar regulatory circuits in other parts of the brain, and they provide new molecular insights into human diseases, Chiang said.

“There is increasing evidence that an imbalance of excitatory and inhibitory neurons plays a critical role in psychiatric and neurodevelopmental disorders including schizophrenia and autism spectrum disorders.”

Defects in Purkinje neurons have been demonstrated histologically in patients with autism spectrum disorders. The current findings suggest that Purkinje defects would disturb the balance of excitatory and inhibitory neurons in the cerebellum.

Chiang and his colleagues showed in earlier studies that Sonic hedgehog is an important signal for the production of neurons in the cerebellum during the first wave of neurogenesis in embryonic development. The current studies implicate the same signaling molecule in the second wave of neurogenesis, which happens in the white matter of the cerebellum during postnatal development.

“We haven’t understood what signals regulate the production of neurons in postnatal cerebellar white matter — and what neurons they give rise to,” Chiang said. “Our study basically provides those answers.”

Next, the group will probe how Sonic hedgehog produced by the Purkinje neurons travels to two different regions of the cerebellum to stimulate neuron proliferation.

“It’s too far to be diffusion; there has to be some active transport system,” Chiang said. “We are fascinated by how Sonic hedgehog travels so far to regulate neuron development.”

Other Vanderbilt authors of the study include Tatiana Ketova, Ph.D., Fong Pan, Ph.D., Christopher Wright, D.Phil., and Ying Litingtung, Ph.D. The research was supported by grants from the National Institutes of Health (CA068485, NS042205).