PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.

Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene-gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and Nrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21-NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.

Amyloid pathology in spinal cord of the transgenic Alzheimer's disease mice is correlated to the corticospinal tract pathway.

The transgenic TgCRND8 mouse is widely used as an animal model of Alzheimer's disease (AD) and exhibits an early onset of senile plaque pathogenesis in the brain. Here we report that TgCRND8 mice also have amyloid-ß (Aß) neuropathology in spinal cord. TgCRND8 mice began to show obvious Aß deposition in both gray matter of dorsal horn and white matter in the central part of dorsal column of the spinal cord at 10 months of age onward. Further experiments showed that the distribution of Aß deposition in the spinal cord corresponds to the corticospinal tract pathway and its projection regions in TgCRND8 mice. We hypothesized that neurons in the sensorimotor cortex is the source of the Aß peptide deposited in the spinal cord of these mice. To test the hypothesis, we ablated the sensorimotor cortex to interrupt connections between the sensorimotor cortex and spinal cord. We found that Aß burden was significantly reduced in the denervated side compared to the contralateral side. Our results suggest that the sensorimotor cortex might be the primary source of Aß in spinal cord of TgCRND8 mice. This is consistent with the observation that the sensorimotor cortex is one region particularly vulnerable during the progression of AD. The characteristics of Aß distribution in TgCRND8 mice suggest that there are other ways related to the formation of Aß plaques in addition to the terminal and synaptic release of Aß.