Biology subjects

Kaslin, J.

Publications and source records attributed to Kaslin, J..

3 recordsLinked to original sources

bioRxiv2018

Tectal stem cells display diverse regenerative capacities

How diverse adult stem and progenitor populations regenerate tissue following damage to the CNS remains unknown across most neurogenic domains. To understand the role of quiescent radial-glial (qRG) stem cells during regeneration, we tested the hypothesis that qRG could be induced to proliferate and produce newborn neurons. We designed a stab lesion assay in the midbrain tectum of the adult zebrafish to target an isolated population of qRG, and investigated their proliferative behaviour, differentiation potential, and requirement of Wnt/{beta}-catenin signalling for the regenerative response. EdU-labelling showed that a small proportion of qRG transit to a proliferative state (pRG), but that progeny of pRG are restricted to a radial-glial fate. Lesion promoted upregulation of proliferation and neurogenesis from neuro-epithelial-like amplifying progenitors (NE-Ap) of the tectal marginal zone (TMZ). Homeostatic levels of Wnt/{beta}-catenin signalling persisted under lesioned conditions in the qRG/pRG population, whereby increased {beta}-catenin staining and axin2 expression was present in the NE-Ap progenitor zone. Attenuation of Wnt signalling using Dickkopf-1, demonstrated that proliferative responses post-injury appeared to be Wnt-independent. Our results align with the emerging view that adult stem/progenitor phenotypes are characterized by discrete, rather than mutual, regenerative programs and that different stem cell domains employ different modes of regeneration.

neuroscience↗

bioRxiv2018

Accelerated brain aging towards transcriptional inversion in a zebrafish model of familial Alzheimer’s disease

Alzheimers disease (AD) develops silently over decades. We cannot easily access and analyse pre-symptomatic brains, so the earliest molecular changes that initiate AD remain unclear. Previously, we demonstrated that the genes mutated in early-onset, dominantly-inherited familial forms of AD (fAD) are evolving particularly rapidly in mice and rats. Fortunately, some non-mammalian vertebrates such as the zebrafish preserve fAD-relevant transcript isoforms of the PRESENILIN (PSEN1 and PSEN2) genes that these rodents have lost. Zebrafish are powerful vertebrate genetic models for many human diseases, but no genetic model of fAD in zebrafish currently exists. We edited the zebrafish genome to model the unique, protein-truncating fAD mutation of human PSEN2, K115fs. Analysing the brain transcriptome and proteome of young (6-month-old) and aged, infertile (24-month-old) wild type and heterozygous fAD-like mutant female sibling zebrafish supports accelerated brain aging and increased glucocorticoid signalling in young fAD-like fish, leading to a transcriptional inversion into glucocorticoid resistance and vast changes in biological pathways in aged, infertile fAD-like fish. Notably, one of these changes involving microglia-associated immune responses regulated by the ETS transcription factor family is preserved between our zebrafish fAD model and human early-onset AD. Importantly, these changes occur before obvious histopathology and likely in the absence of A{beta}. Our results support the contributions of early metabolic and oxidative stresses to immune and stress responses favouring AD pathogenesis and highlight the value of our fAD-like zebrafish genetic model for elucidating early changes in the brain that promote AD pathogenesis. The success of our approach has important implications for future modelling of AD.

bioinformatics↗

bioRxiv2017

Loss Of lrrk2 Impairs Cell Proliferation And Neuronal Regeneration In The Zebrafish Brain

LRRK2 mutations are a major cause of Parkinsons disease. Pathogenicity of LRRK2 loss-of-function is controversial, as knockout in rodents reportedly induces no brain-specific effects and knockdown studies in zebrafish are conflicting. Here we show that CRISPR/Cas9-engineered deletion of the ~60-kbp-long zebrafish lrrk2 locus elicits a pleomorphic, albeit transient brain phenotype in maternal-zygotic mutants (mzLrrk2). Intriguingly, 11-month-old mzLrrk2 adults display increased dopamine and serotonin catabolism. Additionally, we find decreased mitosis in the larval brain and reduced stab injury-induced neuronal regeneration in the adult telencephalon. Finally, hypokinesia associates with loss of lrrk2 in larvae. Our results demonstrate that lrrk2 knockout has an early neurodevelopmental effect, and leads to perturbed dopamine and serotonin catabolism in a LRRK2 knockout. We propose mzLrrk2 zebrafish as a valuable tool to study LRRK2 loss-of-function in vivo, and provide a link between LRRK2 and the control of basal cell proliferation in the brain that may become potentially critical upon challenges like brain injury.

neuroscience↗