The recent successes of genome-wide expression profiling in biology tend to overlook the power of genetics. We here propose a merger of genomics and genetics into ‘genetical genomics’. This involves expression profiling and marker-based fingerprinting of each individual of a segregating population, and exploits all the statistical tools used in the analysis of quantitative trait loci. Genetical genomics will combine the power of two different worlds in a way that is likely to become instrumental in the further unravelling of metabolic, regulatory and developmental pathways.

Genetical genomics : the added value from segregation

Genetic Dissection of Transcriptional Regulation in Budding Yeast

Genome-wide association-, replication-, and neuroimaging study implicates HOMER1 in the etiology of major depression.

Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation.

GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease

Inflammation and apoptosis play important roles in the initiation and progression of acute lung injury (ALI). Our previous study has shown that progranulin (PGRN) exerts lung protective effects during LPS-induced ALI. Here, we have investigated the potential roles of PGRN-targeting microRNAs (miRNAs) in regulating inflammation and apoptosis in ALI and have highlighted the important role of PGRN. LPS-induced lung injury and the protective roles of PGRN in ALI were first confirmed. The function of miR-34b-5p in ALI was determined by transfection of a miR-34b-5p mimic or inhibitor in intro and in vivo. The PGRN level gradually increased and subsequently significantly decreased, reaching its lowest value by 24 hr; PGRN was still elevated compared to the control. The change was accompanied by a release of inflammatory mediators and accumulation of inflammatory cells in the lungs. Using bioinformatics analysis and RT-PCR, we demonstrated that, among 12 putative miRNAs, the kinetics of the miR-34b-5p levels were closely associated with PGRN expression in the lung homogenates. The gain- and loss-of-function analysis, dual-luciferase reporter assays, and rescue experiments confirmed that PGRN was the functional target of miR-34b-5p. Intravenous injection of miR-34b-5p antagomir in vivo significantly inhibited miR-34b-5p up-regulation, reduced inflammatory cytokine release, decreased alveolar epithelial cell apoptosis, attenuated lung inflammation, and improved survival by targeting PGRN during ALI. miR-34b-5p knockdown attenuates lung inflammation and apoptosis in an LPS-induced ALI mouse model by targeting PGRN. This study shows that miR-34b-5p and PGRN may be potential targets for ALI treatments.

miR-34b-5p inhibition attenuates lung inflammation and apoptosis in an LPS-induced acute lung injury mouse model by targeting progranulin.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease characterized by severe dyskinesia due to a progressive loss of dopaminergic neurons along the nigro-striatal pathway. The current focus of treatment is to relieve symptoms through administration of levodopa, such as L-3,4-dihydroxy phenylalanine replacement therapy, dopaminergic agonist administration, functional neurosurgery, and gene therapy, rather than preventing dopaminergic neuronal damage. Hence, the application and development of neuroprotective/disease modification strategies is absolutely necessary. Currently, stem cell therapy has been considered for PD treatment. As for the stem cells, mesenchymal stem cells (MSCs) seem to be the most promising. In this review, we analyze the mechanisms of action of MSCs in Parkinson's disease, including growth factor secretion, exocytosis, and attenuation of neuroinflammation. To determine efficacy and protect patients from possible adverse effects, ongoing rigorous and controlled studies of MSC treatment will be critical.

Clinical potential and current progress of mesenchymal stem cells for Parkinson's disease: a systematic review.

A number of studies have shown that amyloid precursor protein (App) plays a critical role in Alzheimer's disease (AD); however, little is known about the genetic regulatory network. In this study, the authors combined array analysis and quantitative trait loci (QTL) mapping to characterize the genetic variation and genetic regulatory network for App using hippocampus of BXD recombinant inbred (RI) mice. The variation in expression level of App is conspicuous across the 78 BXD RI strains. Moreover, the expression level of App is significantly higher in DBA/2J than the level in C57BL/6J (p < .001). Quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis has further confirmed the significant difference between the two parental strains C57BL/6J and DBA/2J. The authors performed an interval mapping for App gene expression and found that it is cis regulated with highly significant likelihood-ratio statistic (LRS) score (LRS = 19; p < .05). Four SNPs and two InDels (insertions or deletions) were identified in the promoter, and one of the SNPs is located in the pax2 motif. Genetic regulatory network analysis showed that App coregulated with many AD-related genes, including Gsk3b, Falz, Mef2a, Tlk2, Rtn, and Prkca. The genetical genomics approach demonstrates the importance and the potential power of the expression quantitative trait loci (eQTL) studies in identifying regulatory network that contribute to complex traits, such as AD.

https://www.tandfonline.com/doi/pdf/10.1080/03610730903418729

Genetic Regulatory Network Analysis for App Based on Genetical Genomics Approach

A body of evidence has suggested that tissue-engineered nerve grafts hold promise for the surgical repair of spinal cord injuries. In this study, a novel nerve graft was prepared to be implantated into a 5 mm gap which was caused by a complete transection of the rat spinal cord. The graft was featured by incorporation of neurotrophin-3 into a chitosan-based tube scaffold with a spinal cord-mimicking, partition-type architecture, which was prepared based on the morphometric insights of normal spinal cord anatomy. A set of behavioral, functional, and histological examinations were carried out to evaluate the repair. Results from Basso, Beattie, and Bresnahan tests, motor evoked potential measurements, anterograde tracing, and histological analyses suggested that the combined application of chitosan as the scaffold biomaterial, a spinal cord-mimicking partition-type as the scaffold architecture, and neurotrophin-3 (NT-3) as the bioactive component might probably create synergetic promotion on spinal cord reg...

Combined use of spinal cord-mimicking partition type scaffold architecture and neurotrophin-3 for surgical repair of completely transected spinal cord in rats.

SummaryAims
Astroglial-fibrotic scar formation following central nervous system injury can help repair blood-brain barrier and seal the lesion, whereas it also represents a strong barrier for axonal regeneration. Intensive preclinical efforts have been made to eliminate/reduce the inhibitory part and, in the meantime, preserve the beneficial role of astroglial-fibrotic scar.

Methods
In this study, we established an in vitro system, in which coculture of astrocytes and meningeal fibroblasts was treated with exogenous transforming growth factor-β1 (TGF-β1) to form astroglial-fibrotic scar-like cell clusters, and thereby evaluated the efficacy of RNAi targeting ephrin-B2 in preventing scar formation from the very beginning. We further tested the effect of RNAi-based mitigation of astroglial-fibrotic scar on spinal axon outgrowth on a custom-made microfluidic platform.

Results
We found that siRNA targeting ephrin-B2 significantly reduced both the number and the diameter of cell clusters induced by TGF-β1 and diminished the expression of aggrecan and versican in the coculture, and allowed for significantly longer extension of outgrowing spinal cord axons into astroglial-fibrotic scar as assessed on the microfluidic platform.

Conclusions
These results suggest that astroglial-fibrotic scar formation and particularly the expression of aggrecan and versican could be mitigated by ephrin-B2 specific siRNA, thus improving the microenvironment for spinal axon regeneration.

RNAi-mediated ephrin-B2 silencing attenuates astroglial-fibrotic scar formation and improves spinal cord axon growth.

Aims At the beginning of spinal cord injury (SCI), the expression of EphB2 on fibroblasts and ephrin-B2 on astrocytes increased simultaneously and their binding triggers the formation of astroglial-fibrotic scars, which represent a barrier to axonal regeneration. In the present study, we sought to suppress scar formation and to promote recovery from SCI by targeting EphB2 in vivo. Methods The female rats SCI models were used in vivo experiments by subsequently injecting with EphB2 shRNA lentiviruses. The effect on EphB2 knockdown was evaluated at 14 days after injury. The repair outcomes were evaluated at 3 months by electrophysiological and morphological assessments to regenerated nerve tissue. The EphB2 expression and TGF-β1 secretion were detected in vitro using a lipopolysaccharides (LPS)-induced astrocyte injury model. Results RNAi decreased the expression of EphB2 after SCI, which effectively inhibited fibroblasts and astrocytes from aggregating at 14 days. The expression of EphB2 in activated astrocytes, in addition to fibroblasts, was significantly increased after SCI in vivo, in line with upregulated expression of EphB2 and increased secretion of TGF-β1 in astrocyte culture treated with LPS. Compared to the scramble control, RNAi targeting with EphB2 could promote more nerve regeneration and better myelination. Conclusions EphB2 knockdown may effectively inhibit the formation of astroglial-fibrotic scars at the beginning of SCI. It is beneficial to eliminate the barrier of nerve regeneration.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13641

Ying Chen

Papers

Clinical potential and current progress of mesenchymal stem cells for Parkinson's disease: a systematic review.

Genetic Regulatory Network Analysis for App Based on Genetical Genomics Approach

Combined use of spinal cord-mimicking partition type scaffold architecture and neurotrophin-3 for surgical repair of completely transected spinal cord in rats.

RNAi-mediated ephrin-B2 silencing attenuates astroglial-fibrotic scar formation and improves spinal cord axon growth.

EphB2 knockdown decreases the formation of astroglial‐fibrotic scars to promote nerve regeneration after spinal cord injury in rats