Adaptation of short-term plasticity parameters via error-driven learning may explain the correlation between activity-dependent synaptic properties, connectivity motifs and target specificity.

The anatomical connectivity among neurons has been experimentally found to be largely non-random across brain areas. This means that certain connectivity motifs occur at a higher frequency than would be expected by chance. Of particular interest, short-term synaptic plasticity properties were found to colocalize with specific motifs: an over-expression of bidirectional motifs has been found in neuronal pairs where short-term facilitation dominates synaptic transmission among the neurons, whereas an over-expression of unidirectional motifs has been observed in neuronal pairs where short-term depression dominates. In previous work we found that, given a network with fixed short-term properties, the interaction between short- and long-term plasticity of synaptic transmission is sufficient for the emergence of specific motifs. Here, we introduce an error-driven learning mechanism for short-term plasticity that may explain how such observed correspondences develop from randomly initialized dynamic synapses. By allowing synapses to change their properties, neurons are able to adapt their own activity depending on an error signal. This results in more rich dynamics and also, provided that the learning mechanism is target-specific, leads to specialized groups of synapses projecting onto functionally different targets, qualitatively replicating the experimental results of Wang and collaborators

PTEN levels are controlled by a nuclear transport receptor in lung cancer

The maintenance of PTEN protein levels is critical for tumor suppression. Yet, the ubiquitination system has been shown to affect PTEN levels both adversely through degradation, as well as positively through nuclear import, and it has remained unclear how these two processes are integrated to prevent cancer. Here we show, that a nuclear import receptor is at the heart of a failsafe system that maintains PTEN levels by mediating its nuclear transport. Loss of import receptor function not only leads to cytoplasmic PTEN accumulation but also prompts PTEN degradation through a novel component of the PTEN ubiquitination system. By testing the consequences of importin loss in vivo, we found that hypomorphic mice developed lung adenocarcinoma, which presented with aberrant cytoplasmic PTEN localization and degradation, as predicted by our in vitro findings. Since the corresponding human locus suffers frequent deletion as well as inactivating mutations in lung cancer, we propose that this import receptor is a novel tumor suppressor that antagonizes PI 3-Kinase signaling in settings with at least one intact PTEN gene

The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein

Phosphatase and tensin homologue (PTEN) protein levels are critical for tumor suppression. However, the search for a recurrent cancer-associated gene alteration that causes PTEN degradation has remained futile. In this study, we show that Importin-11 (Ipo11) is a transport receptor for PTEN that is required to physically separate PTEN from elements of the PTEN degradation machinery. Mechanistically, we find that the E2 ubiquitin-conjugating enzyme and IPO11 cargo, UBE2E1, are limiting factors for PTEN degradation. Using in vitro and in vivo gene-targeting methods, we show that Ipo11 loss results in degradation of Pten, lung adenocarcinoma, and neoplasia in mouse prostate with aberrantly high levels of Ube2e1 in the cytoplasm. These findings explain the correlation between loss of IPO11 and PTEN protein in human lung tumors. Furthermore, we find that IPO11 status predicts disease recurrence and progression to metastasis in patients choosing radical prostatectomy. Thus, our data introduce the IPO11 gene as a tumor-suppressor locus, which is of special importance in cancers that still retain at least one intact PTEN allele