Regeneration and neural circuits in the spinal cord : an imaging study on zebrafish

The reversal of spinal cord injury (SCI) and its devastating effect on voluntary control is one of the most provocative challenges in neuroscience research. Preclinical and clinical research has for a very long time tried to address this challenge, but there is still no effective treatment that leads to functional recovery. In simplified terms, the spinal cord resembles a highway, with outgoing commands from the brain and incoming feedback from the periphery. However, the spinal cord is an extremely complex apparatus with billions of cells, connections, and neuronal circuits. Injury to the spinal cord in humans has acute disastrous effects, followed by secondary pathophysiological events leading to a permanent loss of sensation and motor function corresponding to the site of injury. The spinal cord of humans, as far as we know, lacks the capacity to regenerate after an injury, in contrast to that of vertebrate fish, such as the zebrafish, which has an extraordinary ability to regenerate. Investigating the regenerative capacity of zebrafish can unveil mechanisms and features that may be translatable to the clinic. In paper I, we identified V2a interneurons as an intrinsic source of excitation and a necessity for the zebrafish larvae’s normal generation of locomotor rhythm. In paper II, we scaled up and developed the technique used in paper I to a robust method to induce precise spatial and temporal SCI with minimal collateral damage in zebrafish larvae. In paper III, we investigated the impact of several factors, including lesion size, hypothermia, and analgesic substances, on the functional recovery of zebrafish larvae following SCI. Furthermore, we examined intrinsic Ca2+ signaling before and after SCI. In summary, this thesis paves the way for further investigations of the remarkable regenerative capacity zebrafish possess

GIT1 protects against breast cancer growth through negative regulation of Notch

Notch signalling is reported to be hyperactivated in oestrogen receptor-negative (ER-) breast cancer. Here the authors show that G protein-coupled receptor kinase-interacting protein 1 (GIT1) negatively regulates Notch signalling and tumour growth in ER- breast cancer by blocking Notch ICD nuclear translocation.Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth.</p

GIT1 protects against breast cancer growth through negative regulation of Notch

Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth

Single cell analysis of autism patient with bi-allelic NRXN1-alpha deletion reveals skewed fate choice in neural progenitors and impaired neuronal functionality

We generated human iPS derived neural stem cells and differentiated cells from healthy control individuals and an individual with autism spectrum disorder carrying bi-allelic NRXN1-alpha deletion. We investigated the expression of NRXN1-alpha during neural induction and neural differentiation and observed a pivotal role for NRXN1-alpha during early neural induction and neuronal differentiation. Single cell RNA-seq pinpointed neural stem cells carrying NRXN1-alpha deletion shifting towards radial glia-like cell identity and revealed higher proportion of differentiated astroglia. Furthermore, neuronal cells carrying NRXN1-alpha deletion were identified as immature by single cell RNA-seq analysis, displayed significant depression in calcium signaling activity and presented impaired maturation action potential profile in neurons investigated with electrophysiology. Our observations propose NRXN1-alpha plays an important role for the efficient establishment of neural stem cells, in neuronal differentiation and in maturation of functional excitatory neuronal cells