Genetic control of Schwann cell differentiation

Schwann cellen myelineren axonen onder de invloed van axonale signalen. Het is nog niet volkomen duidelijk welke signalen dat zijn. Ondanks dat zijn er de laatste jaren wel veel intracellulaire regulatoren van het myelinatie programma geïdentificeerd en bestudeerd. Verschillende factoren die een rol spelen tijdens de ontwikkeling van de myelinerende Schwann cel worden in dit proefschrift beschreven. Twee van de belangrijkste factoren zijn Oct-6 en Krox-20. Wanneer een van beide factoren afwezig is tijdens de ontwikkeling dan vindt er geen myelinatie plaats in de Krox-20 knock-out muis en in de Oct-6 knock-out muis uiteindelijk wel, maar met een flinke vertraging. Omdat er in de Oct-6 mutant uiteindelijk alsnog myelinatie plaatsvindt is er gezocht naar eventuele ander factoren die daar verantwoordelijk voor zouden kunnen zijn. Het blijkt nu als Brn-2 samen met Oct-6 afwezig is tijdens de ontwikkeling van de zenuwen dat dan ook in dit geval geen myelinatie meer optreedt. Wanneer nu overexpressie van Brn-2 in de Oct-6 mutant tot stand wordt gebracht blijkt dat myelinatie van de axonen op bijna het normale niveau plaats vindt. Naast deze Oct-6 en Krox-20 mutanten is er ook nog een natuurlijke mutant clawpaw. Deze mutant vertoont net als de Oct-6 mutant een ernstige vertraging in de myelinatie van de axonen. De natuurlijke mutant clawpaw heeft een afwijkende Lgi4 expressie. Dit kan een indicatie zijn dat Lgi4 betrokken is bij het myelinatie proces in de Schwann cel

On the change of growth and wood constructive substances in Salix Koriyanagi which was grown in different soil moisture conditions

textabstractThe cellular interactions that drive the formation and maintenance of the insulating myelin sheath around axons are only partially understood. Leucine-rich glioma-inactivated (LGI) proteins play important roles in nervous system development and mutations in their genes have been associated with epilepsy and amyelination. Their function involves interactions with ADAM22 and ADAM23 cell surface receptors, possibly in apposing membranes, thus attenuating cellular interactions. LGI4-ADAM22 interactions are required for axonal sorting and myelination in the developing peripheral nervous system (PNS). Functional analysis revealed that, despite their high homology and affinity for ADAM22, LGI proteins are functionally distinct. To dissect the key residues in LGI proteins required for coordinating axonal sorting and myelination in the developing PNS, we adopted a phylogenetic and computational approach and demonstrate that the mechanism of action of LGI4 depends on a cluster of three amino acids on the outer surface of the LGI4 protein, thus providing a structural basis for the mechanistic differences in LGI protein function in nervous system development and evolution

Structural basis for LMO2-driven recruitment of the SCL: E47bHLH heterodimer to hematopoietic-specific transcriptional targets

Cell fate is governed by combinatorial actions of transcriptional regulators assembling into multiprotein complexes. However, the molecular details of how these complexes form are poorly understood. One such complex, which contains the basic-helix-loop-helix heterodimer SCL:E47 and bridging proteins LMO2:LDB1, critically regulates hematopoiesis and induces Tcell leukemia. Here, we report the crystal structure of (SCL:E47)bHLH:LMO2:LDB1LID bound to DNA, providing a molecular account of the network of interactions assembling this complex. This reveals an unexpected role for LMO2. Upon binding to SCL, LMO2 induces new hydrogen bonds in SCL:E47, thereby strengthening heterodimer formation. This imposes a rotation movement onto E47 that weakens the heterodimer:DNA interaction, shifting the main DNA-binding activity onto additional protein partners. Along with biochemical analyses, this illustrates, at an atomic level, how hematopoietic-specific SCL sequesters ubiquitous E47 and associated cofactors and supports SCL'sreported DNA-binding-independent functions. Importantly, this work will drive the design of small molecules inhibiting leukemogenic processes. © 2013 The Authors

SLAIN2 links microtubule plus end–tracking proteins and controls microtubule growth in interphase

SLAIN2’s interactions with multiple different microtubule plus end–tracking proteins stimulate processive microtubule polymerization and ensure proper microtubule organization

Bicaudal D2, Dynein, and Kinesin-1 Associate with Nuclear Pore Complexes and Regulate Centrosome and Nuclear Positioning during Mitotic Entry

Mammalian Bicaudal D2 is the missing molecular link between cytoplasmic motor proteins and the nucleus during nuclear positioning prior to the onset of mitosis

A reference map of murine cardiac transcription factor chromatin occupancy identifies dynamic and conserved enhancers

Mapping the chromatin occupancy of transcription factors (TFs) is a key step in deciphering developmental transcriptional programs. Here we use biotinylated knockin alleles of seven key cardiac TFs (GATA4, NKX2-5, MEF2A, MEF2C, SRF, TBX5, TEAD1) to sensitively and reproducibly map their genome-wide occupancy in the fetal and adult mouse heart. These maps show that TF occupancy is dynamic between developmental stages and that multiple TFs often collaboratively occupy the same chromatin region through indirect cooperativity. Multi-TF regions exhibit features of functional regulatory elements, including evolutionary conservation, chromatin accessibility, and activity in transcriptional enhancer assays. H3K27ac, a feature of many enhancers, incompletely overlaps multi-TF regions, and multi-TF regions lacking H3K27ac retain conservation and enhancer activity. TEAD1 is a core component of the cardiac transcriptional network, co-occupying cardiac regulatory regions and controlling cardiomyocyte-specific gene functions. Our study provides a resource for deciphering the cardiac transcriptional regulatory network and gaining insights into the molecular mechanisms governing heart development

Novel Foxo1-dependent transcriptional programs control Treg cell function

Regulatory T (T(reg)) cells, characterized by expression of the transcription factor forkhead box P3 (Foxp3), maintain immune homeostasis by suppressing self-destructive immune responses. Foxp3 operates as a late-acting differentiation factor controlling T(reg) cell homeostasis and function, whereas the early T(reg)-cell-lineage commitment is regulated by the Akt kinase and the forkhead box O (Foxo) family of transcription factors. However, whether Foxo proteins act beyond the T(reg)-cell-commitment stage to control T(reg) cell homeostasis and function remains largely unexplored. Here we show that Foxo1 is a pivotal regulator of T(reg )cell function. T(reg) cells express high amounts of Foxo1 and display reduced T-cell-receptor-induced Akt activation, Foxo1 phosphorylation and Foxo1 nuclear exclusion. Mice with T(reg)-cell-specific deletion of Foxo1 develop a fatal inflammatory disorder similar in severity to that seen in Foxp3-deficient mice, but without the loss of T(reg) cells. Genome-wide analysis of Foxo1 binding sites reveals ~300 Foxo1-bound target genes, including the pro-inflammatory cytokine Ifng, that do not seem to be directly regulated by Foxp3. These findings show that the evolutionarily ancient Akt-Foxo1 signalling module controls a novel genetic program indispensable for T(reg) cell function