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04-08-2011 | Article

Speech, language function gene modulates neuronal plasticity

Abstract

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MedWire News: Study findings suggest that forkhead-box protein (FOX)P2, a transcription factor associated with speech and language function, modulates neuronal network formation by regulating messenger RNAs involved in the development and plasticity of neuronal connections.

"To our knowledge, the current report represents the first large-scale in vivo characterization of direct and indirect Foxp2 targets in the embryonic brain," say Simon Fisher (University of Oxford, UK) and co-authors.

The findings are of importance as they offer a number of new candidate genes that could be investigated in individuals with speech difficulties. "Our findings shed light on how Foxp2 directs particular features of nervous system development, helping us to build bridges between genes and complex aspects of brain function," say the researchers.

For the study, Fisher and team performed a systematic large-scale in vivo ChIP-chip screen of the embryonic mouse brain, establishing the significance of ChIP results in wild-type mice brains. A set of 264 high-confidence neural targets were thereby identified.

Targets of importance included Pak3, a downstream effector of the Rho family of GTPases playing a critical role in pathways restraining neurite growth; Nptn, encoding a synaptic glycoprotein involved in the development of synaptic connections and long-term plasticity; WAsf1, regulating activity-induced changes in dendritic spine morphogenesis and actin remodelling; the neuronal semphorins Sema4f and Sema6d; and Ywhah, which encodes an adapter protein implicated in presynaptic plasticity.

Among the validated direct targets of Foxp2 identified in the study, the authors also found a number of micro (mi)RNA molecules, including mir-124a and mir-137. miRNAs are abundant in the brain and are implicated in critical aspects of nervous system development and function, playing a pivotal role in processes such as neurite outgrowth, axonal pathfinding and synaptic plasticity.

The study findings also showed that mice with loss of Foxp2 function had significant reductions in neurite outgrowth and decreased synaptic plasticity. Furthermore, Foxp2 was found to directly and indirectly regulate networks of genes responsible for altering the length and branching of neuronal projections - an important route for modulating the wiring of neural connections in the developing brain.

Writing in the journal PLoS Genetics, the team says that the current study findings "will be important for directing follow-up studies of Foxp2-dependent pathways and assessing their involvement in traits such as acquisition of motor skills, vocal learning, and spoken language."

By Ingrid Grasmo