ABC Transporters B1, C1 and G2 Differentially Regulate Neuroregeneration in Mice

Abstract

BackgroundATP-binding cassette (ABC) transporters are essential regulators of organismic homeostasis, and are particularly important in protecting the body from potentially harmful exogenous substances. Recently, an increasing number of in vitro observations have indicated a functional role of ABC transporters in the differentiation and maintenance of stem cells. Therefore, we sought to determine brain-related phenotypic changes in animals lacking the expression of distinct ABC transporters (ABCB1, ABCG2 or ABCC1).Methodology and Principal FindingsAnalyzing adult neurogenesis in ABC transporter-deficient animals in vivo and neuronal stem/progenitor cells in vitro resulted in complex findings. In vivo, the differentiation of neuronal progenitors was hindered in ABC transporter-deficient mice (ABCB10/0) as evidenced by lowered numbers of doublecortin+ (−36%) and calretinin+ (−37%) cells. In vitro, we confirmed that this finding is not connected to the functional loss of single neural stem/progenitor cells (NSPCs). Furthermore, assessment of activity, exploratory behavior, and anxiety levels revealed behavioral alterations in ABCB10/0 and ABCC10/0 mice, whereas ABCG20/0 mice were mostly unaffected.Conclusion and SignificanceOur data show that single ABC transporter-deficiency does not necessarily impair neuronal progenitor homeostasis on the single NSPC level, as suggested by previous studies. However, loss of distinct ABC transporters impacts global brain homeostasis with far ranging consequences, leading to impaired neurogenic functions in vivo and even to distinct behavioral phenotypes. In addition to the known role of ABC transporters in proteopathies such as Parkinson's disease and Alzheimer's disease, our data highlight the importance of understanding the general function of ABC transporters for the brain's homeostasis and the regeneration potential.

High Mobility Group N Proteins Modulate the Fidelity of the Cellular Transcriptional Profile in a Tissue- and Variant-specific Manner

“…Thus, the thyroid hormone receptor Tshr and PomC, a polypeptide hormone precursor that controls feeding and body weight (59), are down-regulated in Hmgn3 tm1/tm1 brain tissue, and Trib3, a putative protein kinase, implicated in hyperglycemia and glucose intolerance (60, 61) is down-regulated in the Hmgn3 tm1/tm1 liver. Muscle tissues were not analyzed in Hmgn3 tm1/tm1 mice in this study, and only weak expression was previously reported in skeletal muscle (50). The reduced grip strength detected only in Hmgn3tm1/tm1 mouse mutants could therefore be a secondary effect to differences in energy metabolism found in these mutants and not in Hmgn1 tm1/tm1 or Hmgn5 tm1/tm1 mice.…”

“…The potentially altered neuronal differentiation could be directly connected to the behavioral phenotype of the Hmgn1 tm1/tm1 mice shown in Table 1. It has recently been demonstrated that modified levels of neuronal progenitor differentiation can be associated with modified levels of exploratory activity akin to the rearing/exploration phenotype observed here (50 mice. In addition, Hmgn1 tm1/tm1 mice are deficient in the repair of damaged DNA leading to hypersensitivity to both UV and ionizing radiation and to an increased incidence of certain tumors (20,21).…”

Metabolic Biomarkers and Neurodegeneration: A Pathway Enrichment Analysis of Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

“…ABC transporters mediate the export of numerous substances (peptides, drugs or drug conjugates, and hydrophobic molecules) through the blood-brain barrier, and they are expressed in each cell type in the brain (Pahnke et al, 2014;Schumacher et al, 2012). The relationship between ABC transporters and neurodegenerative diseases was commonly based on the function of ABC transporters or impairment of their function in the blood-brain barrier.…”

Spinal cord pathology in chronic experimentalToxoplasma gondiiinfection

“…Paraffi n-embedded, 4-μm-thick sections were deparaffi nized and conventionally stained with hematoxylin-eosin (H&E) stain. Immunohistochemical analysis was performed according to our previous publications [52][53][54][55][56][57][58] using a BOND-MAX (Leica Microsystems GmbH/Menarini, Germany) with antibodies against ionized calcium-binding adapter molecule 1 (IBA1, 1:2,000, Wako 019-19741, Germany) to label microglia, glialfi brillary acid protein (GFAP, 1:1,000, DAKO Z033401, Germany) to label astrocytes, myelinbasic protein (MBP, 1:1,600, DAKO A062301, Germany) to label myelin sheets, neurofi lament (NF200; 1:160, Sigma-Aldrich N4142-.5ML, Germany) to label axons, NeuN (1:1,000, Millipore MAB377, Germany) to label neurons, and anti-Toxo (1:200, Dianova DLN-16734, Germany) to label T. gondii. Slides were developed using the Bond™ Polymer Refi ne Detection kit (Menarini/Leica, Germany).…”