Intrinsic control of DRG sensory neuron diversification by Pten.

ABSTRACT

Phosphatase and tensin homolog (PTEN) modulates intracellular survival and differentiation signaling pathways downstream of neurotrophin receptors in the developing peripheral nervous system (PNS). Although well-studied in the context of brain development, our understanding of the in vivo role of PTEN in the PNS is limited to models of neuropathic pain and nerve injury. Here, we assessed how alterations in PTEN signaling affects the development of peripheral somatosensory circuits. We found that sensory neurons within the dorsal root ganglia (DRG) in Pten heterozygous ( Pten Het ) mice exhibit defects in neuronal subtype diversification. Abnormal DRG differentiation in Pten Het mice arises early in development, with subsets of neurons expressing both progenitor and neuronal markers. DRGs in Pten Het mice show dysregulation of both mTOR and GSK-3ß signaling pathways downstream of PTEN. Finally, we show that mice with an autism-associated mutation in Pten ( Pten Y68H/+ ) show abnormal DRG development. Thus, we have discovered a crucial role for PTEN signaling in the intrinsic diversification of primary sensory neuron populations in the DRG during development.