methods-for-modulation-analysis-nf-b-dependent-adult

Methods for the Modulation and Analysis of NF-&#954;B-dependent Adult Neurogenesis

The hippocampus plays a pivotal role in the formation and consolidation of episodic memories, and in spatial orientation. Historically, the adult ...

University of Bielefeld

The mouse mutant "motoneuron disease 2" (MND2, mnd2 on Chr 6) was originally characterized as a spinal muscular atrophy (SMA) because degenerating motoneurons were observed in late stages of the disease. MND2 mutants exhibit a progressive phenotype with neurological symptoms that begin at postnatal day (dP) 20 and include involuntary movements, abnormal postures, akinesis, and death between dP 30 and 40. Unexpectedly, there was no induction of acetylcholine receptor alpha subunit mRNA in skeletal muscle of MND2 mice, an indicator of muscle denervation due to motoneuron loss. Rather, we found a massive loss of striatal neurons beginning at dP 25. Histochemical and ultrastructural analysis revealed nuclear pyknosis, chromatin condensation, and organelle disintegration, combined features of apoptosis and necrosis, characteristic for excitotoxic cell death. Striatal neurodegeneration was accompanied by a pronounced astrogliosis and activation of microglia with macrophage morphology. Motor abnormalities and neuronal loss in MND2 mice were not prevented by neuronal overexpression of a Bcl-2 transgene. Transcripts of several cytokines, including Interleukin-1beta and tumor necrosis factor alpha, were upregulated in the CNS, as well as in lung and spleen, indicating that the mnd2 mutation causes additional pathological effects outside the CNS. Since a 50% reduction in the number of striatal neurons is sufficient to account for the neurological phenotype of MND2 mice, MND2 may be classified as striatal atrophy rather than a primary motor neuron disease. Thus, MND2 mutant mice may provide useful insights into molecular events underlying striatal cell death.

Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2.

products of the dystrophin gene range from the 427-kDa full-length dystrophin to the 70.8-kDa Dp71. Dp427 is expressed in skeletal muscle, where it links the actin cytoskeleton with the extracellular matrix via a complex of dystrophin-associated proteins (DAPs). Dystrophin deficiency disrupts the DAP complex and causes muscular dystrophy in humans and the mdx mouse. Dp71, the major nonmuscle product, consists of the COOH-terminal part of dystrophin, including the binding site for the DAP complex but lacks binding sites for microfilaments. Dp71 transgene (Dp71tg) expressed in mdx muscle restores the DAP complex but does not prevent muscle degeneration. In wild-type (WT) mouse muscle, Dp71tg causes a mild muscular dystrophy. In this study, we tested, using isolated extensor digitorum longus muscles, whether Dp71tg exerts acute influences on force generation and sarcolemmal stress resistance. In WT muscles, there was no effect on isometric twitch and tetanic force generation, but with a cytomegalovirus promotor-driven transgene, contraction with stretch led to sarcolemmal ruptures and irreversible loss of tension. In MDX muscle, Dp71tg reduced twitch and tetanic tension but did not aggravate sarcolemmal fragility. The adverse effects of Dp71 in muscle are probably due to its competition with dystrophin and utrophin (in MDX muscle) for binding to the DAP complex.

Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle.

Muscular dysgenesis (mdg) in the mouse is a loss-of-function mutation of the skeletal muscle isoform of the voltage-sensor Ca2+ channel of skeletal muscle (DHP receptor alpha1 subunit, Cchl1a3, Chr1), which is essential for excitation-contraction coupling. Affected individuals (genotype mdg/mdg, phenotype MDG) are unable to breathe and die perinatally. We introduce here extraocular muscles in the study of MDG myopathy and show that, despite their developmental origin from head placodes, they are affected like trunk and limb muscles. MDG myotubes in situ are eliminated by necrosis, not apoptosis.

Elimination by necrosis, not apoptosis, of embryonic extraocular muscles in the muscular dysgenesis mutant of the mouse.

Chronic heart failure is a multifactorial, progressive disease of many causes and is associated with complex ventricular remodeling. Deposition of extracellular matrix proteins and sarcomeric disarray of the myocytes occur in end-stage heart failure. Ventricular assist devices (VAD), implanted as bridge to transplantation, may reverse ventricular remodeling. Although successfully weaning patients from VAD support has been reported, it is not clear to what degree reversal of remodeling occurs in unloaded failing hearts. Because collagen deposition and ultrastructural disarray are hallmarks of myocardial remodeling, we analyzed the myocardial ultrastructure and collagen content of VAD-supported hearts before and after mechanical unloading.

The structural examination of myocardial samples from patients with end-stage heart failure supported by ventricular assist devices using electron microscopy and amino acid analysis reveals low degree of reverse remodeling.

Vacuolar-vesicular protein sorting (Vps) factors are involved in vesicular trafficking in eukaryotic cells. We identified the missense mutation L967Q in Vps54 in the wobbler mouse, an animal model of amyotrophic lateral sclerosis, and also characterized a lethal allele, Vps54(beta-geo). Motoneuron survival and spermiogenesis are severely compromised in the wobbler mouse, indicating that Vps54 has an essential role in these processes.

Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse.

This is a summary of the presentations and discussion of Panel 2.9, Repair and Recovery of Health Systems of the Conference, Health Aspects of the Tsunami Disaster in Asia, convened by the World Health Organization (WHO) in Phuket, Thailand, 04-06 May 2005. The topics discussed included issues related to the repair and recovery of health systems as pertain to the damage created by the Tsunami. It is presented in the following major sections: (1) needs assessment; (2) coordination; (3) filling gaps; (4) capacity building; (5) what was done well, and what should have been done better; (6) lessons learned; and (7) recommendations. Recommendations included: (1) how to make health systems better prepared for coping with disasters; and (2) how to support preparedness in local communities.

Panel 2.9: repair and recovery of health systems.

Providing health care effectively and efficiently involves putting together a great variety of resource inputs. Inputs or health technologies (HT) are human and physical resources - facilities and equipment, and consumables including pharmaceuticals. In the complex health system environment, this wide range of technologies and related interventions produce an extraordinary array of different service outputs. The World Health Organization (WHO) embarked in mid-1990s on a major research and development initiative to design a methodology and tool that would allow for optimal, rational and systematic planning and management of healthcare technology interventions. These efforts culminated in the development of the Essential Healthcare Technology Package (EHTP),which has since been successfully applied in countries and by several WHO Technical Programs.

EHTP: improving health quality through health technology.

The cause of sporadic amyotrophic lateral sclerosis (ALS) is largely unknown but hypotheses about disease mechanisms include oxidative stress, defective axonal transport, mitochondrial dysfunction and disrupted RNA processing. Whereas familial ALS is well represented by transgenic mutant SOD1 mouse models, the mouse mutant wobbler (WR) develops progressive motor neuron degeneration due to a point mutation in the Vps54 gene, and provides an animal model for sporadic ALS. VPS54 protein as a component of a protein complex is involved in vesicular Golgi trafficking; impaired vesicle trafficking might also be mechanistic in the pathogenesis of human ALS.

Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease.

Adult neural crest related-stem cells persist in adulthood, making them an ideal and easily accessible source of multipotent cells for potential clinical use. Recently, we reported the presence of neural crest-related stem cells within adult palatal ridges, thus raising the question of their localization in their endogenous niche. Using immunocytochemistry, reverse transcription-polymerase chain reaction, and correlative fluorescence and transmission electron microscopy, we identified myelinating Schwann cells within palatal ridges as a putative neural crest stem cell source. Palatal Schwann cells expressed nestin, p75(NTR), and S100. Correlative fluorescence and transmission electron microscopy revealed the exclusive nestin expression within myelinating Schwann cells. Palatal neural crest stem cells and nestin-positive Schwann cells isolated from adult sciatic nerves were able to grow under serum-free conditions as neurospheres in presence of FGF-2 and EGF. Spheres of palatal and sciatic origin showed overlapping expression pattern of neural crest stem cell and Schwann cell markers. Expression of the pluripotency factors Sox2, Klf4, c-Myc, Oct4, the NF-κB subunits p65, p50, and the NF-κB-inhibitor IκB-β were up-regulated in conventionally cultivated sciatic nerve Schwann cells and in neurosphere cultures. Finally, neurospheres of palatal and sciatic origin were able to differentiate into ectodermal, mesodermal, and endodermal cell types emphasizing their multipotency. Taken together, we show that nestin-positive myelinating Schwann cells can be reprogrammed into multipotent adult neural crest stem cells under appropriate culture conditions.

Schwann cells can be reprogrammed to multipotency by culture.

Erwachsener menschlicher Neuralleiste Stammzellen (NCSCs) sind au&szlig;erordentliche hohe Plastizit&auml;t und vielversprechende Kandidaten f&uuml;r den Einsatz in der regenerativen Medizin. Hier beschreiben wir erstmals neuartige Neuralleiste gewonnenen Stammzellen Einwohner innerhalb der respiratorischen Epithel menschlichen Erwachsenen minderwertigen turbinate. Im Gegensatz zu &uuml;berlegen und mittleren Nasenmuschel k&ouml;nnten hohe Mengen an Ausgangsmaterial von menschlichen minderwertig Nasenmuschel isoliert werden. Minimal-invasive Chirurgie Methoden Isolation verwenden ist effizient, selbst bei &auml;lteren Patienten. Innerhalb ihrer endogenen Nische ausgedr&uuml;ckt minderwertig turbinate Stammzellen (ITSCs) hohe nestin, p75(NTR) und S100. Immunoelectron Mikroskopie mit Anti-p75 Antik&ouml;rper angezeigt, dass ITSCs Gliazellen Ursprungs sind und eng mit Nonmyelinating Schwann-Zellen. Kultivierte ITSCs waren positiv f&uuml;r nestin und S100 und die Neuralleiste Marker Slug und SOX10. Gesamten Genoms Microarray Analyse zeigte ausgepr&auml;gte Unterschiede zum menschlichen ES Zellen in Bezug auf Pluripotenz Marker OCT4, SOX2, LIN28 und NANOG, w&auml;hrend Ausdruck von WDR5, KLF4 und c-MYC fast &auml;hnlich war. ITSCs waren in der Lage, in Zellen mit Neuro-ektodermale und mesodermale Ph&auml;notyp zu unterscheiden. Zus&auml;tzlich k&ouml;nnen ITSCs &uuml;berleben und f&uuml;hren Neuralleiste typische Kette Migration in-vivo wenn in H&uuml;hnerembryos transplantiert. Jedoch bilden die ITSCs in schweren kombinierten immungeschw&auml;chte M&auml;use nicht Teratome. Schlie&szlig;lich entwickelten wir eine Trennung-Strategie basierend auf magnetischen Zellsortierung von p75(NTR) positive ITSCs, die gr&ouml;&szlig;eren Neurospheres gebildet und vermehren sich schneller als p75(NTR) negative ITSCs. Zusammengenommen beschreibt unsere Studie, ein Roman, leicht zug&auml;nglichen Quelle von multipotenten menschlichen NCSCs f&uuml;r potenzielle-Zelle-Ersatz-Therapie.

Isolierung von Roman multipotenten Neuralleiste Stammzellen von Erwachsenen menschlichen minderwertigen turbinate.

&#x6210;&#x4EBA;&#x6E90;&#x6027;&#x795E;&#x7ECF;&#x5D74;&#x5E72;&#x7EC6;&#x80DE; (NCSCs) &#x662F;&#x7279;&#x522B;&#x9AD8;&#x7684;&#x53EF;&#x5851;&#x6027;&#x548C;&#x6709;&#x5E0C;&#x671B;&#x7684;&#x5019;&#x9009;&#x4EBA;&#xFF0C;&#x4EE5;&#x4F9B;&#x5728;&#x518D;&#x751F;&#x533B;&#x5B66;&#x4E2D;&#x3002;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x4ECB;&#x7ECD;&#x7B2C;&#x4E00;&#x6B21;&#x5728;&#x547C;&#x5438;&#x9053;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#x5185;&#x7684;&#x4EBA;&#x7C7B;&#x6210;&#x4EBA;&#x4E0B;&#x9F3B;&#x7532;&#x7684;&#x65B0;&#x578B;&#x795E;&#x7ECF;&#x5D74;&#x5E72;&#x7EC6;&#x80DE;&#x4EBA;&#x53E3;&#x3002;&#x4E0E;&#x4E0A;&#x7EA7;&#x548C;&#x4E2D;&#x95F4;&#x9F3B;&#x7532;&#x9AD8;&#x6570;&#x91CF;&#x7684;&#x6E90;&#x6750;&#x6599;&#x80FD;&#x8131;&#x79BB;&#x4EBA;&#x7C7B;&#x4E0B;&#x9F3B;&#x7532;&#x3002;&#x4F7F;&#x7528;&#x5FAE;&#x521B;&#x624B;&#x672F;&#x65B9;&#x6CD5;&#x9694;&#x79BB;&#x662F;&#x8001;&#x5E74;&#x60A3;&#x8005;&#x6709;&#x6548;&#x3002;&#x5185;&#x5176;&#x5185;&#x6E90;&#x6027;&#x7684;&#x5229;&#x57FA;&#xFF0C;&#x52A3;&#x8D28;&#x9F3B;&#x7532;&#x5E72;&#x7EC6;&#x80DE; (ITSCs) &#x8868;&#x793A;&#x5DE2;&#x3001; p75(NTR) &#x548C; S100 &#x7684;&#x9AD8;&#x7684;&#x6C34;&#x5E73;&#x3002;&#x4F7F;&#x7528;&#x6297; p75 &#x6297;&#x4F53;&#x7684;&#x514D;&#x75AB;&#x7535;&#x955C;&#x6280;&#x672F;&#x663E;&#x793A; ITSCs &#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x6765;&#x6E90;&#x548C; nonmyelinating &#x96EA;&#x65FA;&#x7EC6;&#x80DE;&#x5BC6;&#x5207;&#x76F8;&#x5173;&#x3002;&#x8015;&#x5730;&#x7684; ITSCs &#x5DE2;&#x86CB;&#x767D;&#x548C; S100 &#x548C;&#x8F85;&#x52A9;&#x4FE1;&#x606F;&#x533A;&#x548C; SOX10 &#x7684;&#x795E;&#x7ECF;&#x5D74;&#x6807;&#x8BB0;&#x4E3A;&#x9633;&#x6027;&#x3002;&#x5168;&#x57FA;&#x56E0;&#x7EC4;&#x57FA;&#x56E0;&#x82AF;&#x7247;&#x5206;&#x6790;&#x8868;&#x660E;&#x8BC4;&#x9009;&#x6807;&#x8BB0; OCT4&#x3001; SOX2&#x3001; LIN28 &#x548C; NANOG&#xFF0C;&#x5C0A;&#x91CD;&#x5BF9;&#x4EBA;&#x7C7B;&#x80DA;&#x80CE;&#x5E72;&#x7EC6;&#x80DE;&#x5B58;&#x5728;&#x660E;&#x663E;&#x7684;&#x5DEE;&#x5F02;&#xFF0C;&#x800C; WDR5&#x3001; KLF4 &#x548C; C-MYC &#x7684;&#x8868;&#x8FBE;&#x662F;&#x51E0;&#x4E4E;&#x7C7B;&#x4F3C;&#x3002;ITSCs &#x90FD;&#x80FD;&#x5206;&#x5316;&#x7EC6;&#x80DE;&#x4E0E;&#x795E;&#x7ECF;&#x5916;&#x80DA;&#x5C42;&#x548C;&#x4E2D;&#x80DA;&#x53F6;&#x7684;&#x8868;&#x578B;&#x3002;&#x6B64;&#x5916;&#xFF0C;ITSCs &#x90FD;&#x80FD;&#x591F;&#x751F;&#x5B58;&#x4E0B;&#x6765;&#xFF0C;&#x6267;&#x884C;&#x65F6;&#x79FB;&#x690D;&#x5230;&#x9E21;&#x80DA;&#x80CE;&#x4F53;&#x5185;&#x795E;&#x7ECF;&#x5D74;&#x5178;&#x578B;&#x94FE;&#x8FC1;&#x79FB;&#x3002;&#x4E0D;&#x8FC7; ITSCs &#x4E0D;&#x4F1A;&#x5F62;&#x6210;&#x7578;&#x80CE;&#x7624;&#x4E25;&#x91CD;&#x8054;&#x5408;&#x514D;&#x75AB;&#x7F3A;&#x9677;&#x5C0F;&#x9F20;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x6211;&#x4EEC;&#x5236;&#x5B9A;&#x4E86;&#x57FA;&#x4E8E;&#x78C1;&#x6027;&#x7EC6;&#x80DE;&#x5206;&#x9009;&#x5206;&#x79BB;&#x6218;&#x7565;&#x79EF;&#x6781; ITSCs&#xFF0C;&#x5F62;&#x6210;&#x8F83;&#x5927;&#x7684;&#x7403;&#x5185;&#x6269;&#x6563;&#xFF0C;&#x6BD4; p75(NTR) &#x66F4;&#x5FEB;&#x7684; p75(NTR) &#x8D1F; ITSCs&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x4E24;&#x8005;&#x5408;&#x8BA1;&#x4ECB;&#x7ECD;&#x65B0;&#x9896;&#x3001; &#x65B9;&#x4FBF;&#x6765;&#x6E90;&#x7684;&#x591A;&#x80FD;&#x5E72;&#x7684;&#x4EBA; NCSCs&#xFF0C;&#x6F5C;&#x5728;&#x7684;&#x7EC6;&#x80DE;&#x66FF;&#x4EE3;&#x7597;&#x6CD5;&#x3002;

&#x65B0;&#x578B;&#x591A;&#x80FD;&#x5E72;&#x6E90;&#x6027;&#x795E;&#x7ECF;&#x5D74;&#x5E72;&#x7EC6;&#x80DE;&#x7684;&#x5206;&#x79BB;&#x4ECE;&#x6210;&#x4EBA;&#x4EBA;&#x4E0B;&#x9F3B;&#x7532;&#x3002;

Adult human neural crest-derived stem cells (NCSCs) are of extraordinary high plasticity and promising candidates for the use in regenerative medicine. Here we describe for the first time a novel neural crest-derived stem cell population within the respiratory epithelium of human adult inferior turbinate. In contrast to superior and middle turbinates, high amounts of source material could be isolated from human inferior turbinates. Using minimally-invasive surgery methods isolation is efficient even in older patients. Within their endogenous niche, inferior turbinate stem cells (ITSCs) expressed high levels of nestin, p75(NTR), and S100. Immunoelectron microscopy using anti-p75 antibodies displayed that ITSCs are of glial origin and closely related to nonmyelinating Schwann cells. Cultivated ITSCs were positive for nestin and S100 and the neural crest markers Slug and SOX10. Whole genome microarray analysis showed pronounced differences to human ES cells in respect to pluripotency markers OCT4, SOX2, LIN28, and NANOG, whereas expression of WDR5, KLF4, and c-MYC was nearly similar. ITSCs were able to differentiate into cells with neuro-ectodermal and mesodermal phenotype. Additionally ITSCs are able to survive and perform neural crest typical chain migration in vivo when transplanted into chicken embryos. However ITSCs do not form teratomas in severe combined immunodeficient mice. Finally, we developed a separation strategy based on magnetic cell sorting of p75(NTR) positive ITSCs that formed larger neurospheres and proliferated faster than p75(NTR) negative ITSCs. Taken together our study describes a novel, readily accessible source of multipotent human NCSCs for potential cell-replacement therapy.

Isolation of novel multipotent neural crest-derived stem cells from adult human inferior turbinate.

Adultes humains cr&ecirc;te neurale-cellules souches d&eacute;riv&eacute;es (SNCLC) sont de l&#39;extraordinaire plasticit&eacute; &eacute;lev&eacute;e et des candidats prometteurs pour l&#39;utilisation en m&eacute;decine r&eacute;g&eacute;n&eacute;rative. Nous d&eacute;crivons ici pour la premi&egrave;re fois les cellules souches d&eacute;riv&eacute;es de cr&ecirc;te neurale roman habitants au sein de l&#39;&eacute;pith&eacute;lium respiratoire humain adulte inf&eacute;rieure cornet. Par contraste avec les cornets sup&eacute;rieurs et moyens, grande quantit&eacute; de mati&egrave;re d&#39;origine pouvait &ecirc;tre isol&eacute;es des cornets inf&eacute;rieurs humaines. L&#39;utilisation d&#39;isolement de m&eacute;thodes de chirurgie mini-invasive est efficace m&ecirc;me chez les patients plus &acirc;g&eacute;s. Au sein de leur niche endog&egrave;ne, les cellules souches cornets inf&eacute;rieurs (ITSCs) a exprim&eacute; des niveaux &eacute;lev&eacute;s de nestin, p75(NTR) et S100. Immunomicroscopie &eacute;lectronique utilisant des anticorps anti-p75 affich&eacute; que les ITSCs sont d&#39;origine gliale et &eacute;troitement li&eacute; &agrave; la nonmyelinating des cellules de Schwann. ITSCs cultiv&eacute;es &eacute;taient positifs pour nestin et S100 et les marqueurs de la cr&ecirc;te neurale Slug et SOX10. Analyse du g&eacute;nome entier microarray ont montr&eacute; des diff&eacute;rences marqu&eacute;es pour les cellules ES humaines en ce qui concerne les marqueurs de pluripotence OCT4, SOX2, LIN28 et NANOG, tandis que l&#39;expression de WDR5, KLF4 et c-MYC &eacute;tait presque similaire. ITSCs pouvaient se diff&eacute;rencier en cellules neuro-ectodermiques et m&eacute;sodermiques ph&eacute;notype. En outre, ITSCs sont capables de survivre et d&#39;effectuer la migration en cha&icirc;ne typique cr&ecirc;te neurale in vivo lorsque transplant&eacute;s dans des embryons de poulet. Toutefois, ITSCs ne forment pas de t&eacute;ratomes dans des souris immunod&eacute;ficientes combin&eacute;es s&eacute;v&egrave;res. Enfin, nous avons d&eacute;velopp&eacute; une strat&eacute;gie de s&eacute;paration bas&eacute;e sur le tri cellulaire magn&eacute;tique de p75(NTR) positives ITSCs form&eacute; des grandes neurospheres et prolif&egrave;rent plus vite que p75(NTR) n&eacute;gatif ITSCs. Ensemble notre &eacute;tude d&eacute;crit un roman, une source facilement accessible de multipotentes SNCLC humain pour th&eacute;rapie potentielle de cellules de remplacement.

Isolement de nouveaux d&eacute;riv&eacute;s de cr&ecirc;te neurale cellules souches multipotentes d&#39;adulte humaine inf&eacute;rieure cornet.

Umane derivato da cresta neurale cellule staminali adulte (NCSCs) sono di straordinaria alta plasticit&agrave; e promettenti per l&#39;uso in medicina rigenerativa. Qui descriviamo per la prima volta una popolazione romanzo cellule staminali derivate da cresta neurale all&#39;interno dell&#39;epitelio respiratorio umano adulto inferiore dei turbinati. A differenza dei turbinati superiore e medio, quantit&agrave; elevate di materiale di origine potrebbe essere isolato da umano turbinati inferiori. Tramite l&#39;isolamento di metodi di chirurgia mini-invasiva &egrave; efficace anche nei pazienti pi&ugrave; anziani. All&#39;interno della loro nicchia endogena, turbinate inferiore le cellule staminali (ITSCs) espresso alti livelli di nestina, p75(NTR) e S100. Immunoelectron microscopy usando gli anticorpi anti-p75 visualizzato che ITSCs sono di origine gliale e strettamente a nonmyelinating le cellule di Schwann. ITSCs coltivate erano positivi per la nestina e S100 e i marcatori della cresta neurale Slug e SOX10. Analisi di microarray intero genoma ha mostrato differenze marcate di cellule ES umane rispetto ai marcatori di pluripotenza OCT4, SOX2, LIN28 e NANOG, considerando che l&#39;espressione di c-MYC, KLF4 e WDR5 era quasi simile. ITSCs sono stati in grado di differenziarsi in cellule con fenotipo neuro-ectodermica e mesodermica. ITSCs sono inoltre in grado di sopravvivere e di eseguire la migrazione di catena tipica cresta neurale in vivo quando trapiantato in embrioni di pollo. Tuttavia ITSCs non forma teratomi in topi immunodeficienti combinati gravi. Infine, abbiamo sviluppato una strategia di separazione basata sull&#39;ordinamento magnetico delle cellule del p75(NTR) ITSCs positivi che formano grandi neurospheres e proliferavano pi&ugrave; veloce di p75(NTR) negativo ITSCs. Presi nel loro insieme il nostro studio descrive un romanzo, facilmente accessibile fonte di multipotenti NCSCs umano per potenziale terapia di sostituzione delle cellule.

Isolamento del romanzo derivato da cresta neurale cellule staminali multipotenti da adulto umano inferiore dei turbinati.

&#x5927;&#x4EBA;&#x795E;&#x7D4C;&#x5824;&#x7531;&#x6765;&#x306E;&#x5E79;&#x7D30;&#x80DE; (NCSCs) &#x7279;&#x5225;&#x306A;&#x9AD8;&#x3044;&#x53EF;&#x5851;&#x6027;&#x3068;&#x4F7F;&#x7528;&#x3059;&#x308B;&#x305F;&#x3081;&#x306E;&#x6709;&#x671B;&#x306A;&#x5019;&#x88DC;&#x306E;&#x518D;&#x751F;&#x533B;&#x7642;&#x306E;&#x3067;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x3001;&#x65B0;&#x898F;&#x795E;&#x7D4C;&#x5824;&#x7531;&#x6765;&#x5E79;&#x7D30;&#x80DE;&#x96C6;&#x56E3;&#x547C;&#x5438;&#x4E0A;&#x76AE;&#x5185;&#x4EBA;&#x9593;&#x5927;&#x4EBA;&#x4E0B;&#x9F3B;&#x7532;&#x4ECB;&#x306E;&#x521D;&#x3081;&#x3066;&#x3092;&#x8AAC;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;&#x512A;&#x308C;&#x305F;&#x304A;&#x3088;&#x3073;&#x4E2D;&#x9593;&#x7532;&#x306E;&#x3068;&#x306F;&#x5BFE;&#x7167;&#x7684;&#x306B;&#x3001;&#x30BD;&#x30FC;&#x30B9;&#x306E;&#x6750;&#x6599;&#x306E;&#x5927;&#x91CF;&#x4EBA;&#x9593;&#x306E;&#x52A3;&#x308B;&#x7532;&#x4ECB;&#x304B;&#x3089;&#x5206;&#x96E2;&#x3055;&#x308C;&#x305F;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x307E;&#x3059;&#x3002;&#x4F4E;&#x4FB5;&#x8972;&#x624B;&#x8853;&#x6CD5;&#x306E;&#x5206;&#x96E2;&#x306F;&#x3001;&#x9AD8;&#x9F62;&#x306E;&#x60A3;&#x8005;&#x306B;&#x3082;&#x52B9;&#x7387;&#x7684;&#x3067;&#x3059;&#x3002;&#x305D;&#x306E;&#x5185;&#x56E0;&#x6027;&#x306E;&#x30CB;&#x30C3;&#x30C1;&#x306B;&#x4E0B;&#x9F3B;&#x7532;&#x4ECB;&#x5E79;&#x7D30;&#x80DE; (ITSCs) &#x9AD8;&#x30EC;&#x30D9;&#x30EB;&#x306E;&#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x3001;p75(NTR)&#x3001;S100 &#x3092;&#x8868;&#x660E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x53CD; p75 &#x6297;&#x4F53;&#x3092;&#x7528;&#x3044;&#x305F;&#x514D;&#x75AB;&#x96FB;&#x5B50;&#x9855;&#x5FAE;&#x93E1; ITSCs &#x306F;&#x306E;&#x8D77;&#x6E90;&#x306E;&#x30B0;&#x30EA;&#x30A2; &#x30B7;&#x30E5;&#x30EF;&#x30F3;&#x7D30;&#x80DE;&#x306E;&#x5BC6;&#x63A5;&#x306B;&#x95A2;&#x9023;&#x3057;&#x3066; nonmyelinating &#x306B;&#x8868;&#x793A;&#x3002;&#x683D;&#x57F9; ITSCs &#x30CD;&#x30B9;&#x30C1;&#x30F3;&#x3067; S100 &#x3068;&#x795E;&#x7D4C;&#x306E;&#x9802;&#x4E0A;&#x306E;&#x30DE;&#x30FC;&#x30AB;&#x30FC; &#x30B9;&#x30E9;&#x30B0;&#x3068; SOX10 &#x306E;&#x305F;&#x3081;&#x306B;&#x967D;&#x6027;&#x3092;&#x793A;&#x3057;&#x305F;.WDR5&#x3001;KLF4&#x3001;C-MYC &#x306E;&#x767A;&#x73FE;&#x306F;&#x307B;&#x307C;&#x540C;&#x69D8;&#x3067;&#x3042;&#x3063;&#x305F;&#x306B;&#x5BFE;&#x3057;&#x5168;&#x30B2;&#x30CE;&#x30E0;&#x306E;&#x30DE;&#x30A4;&#x30AF;&#x30ED; &#x30A2;&#x30EC;&#x30A4;&#x306E;&#x5206;&#x6790;&#x306F;&#x591A;&#x80FD;&#x6027;&#x30DE;&#x30FC;&#x30AB;&#x30FC; OCT4, SOX2&#x3001;LIN28&#x3001;NANOG&#x3001;&#x70B9;&#x3067;&#x30D2;&#x30C8; ES &#x7D30;&#x80DE;&#x306E;&#x9855;&#x8457;&#x306A;&#x9055;&#x3044;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002;ITSCs &#x795E;&#x7D4C;&#x5916;&#x80DA;&#x8449;&#x3001;&#x4E2D;&#x80DA;&#x8449;&#x6027;&#x8868;&#x73FE;&#x578B;&#x3068;&#x7D30;&#x80DE;&#x306B;&#x5206;&#x5316;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3067;&#x304D;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B; ITSCs &#x306F;&#x751F;&#x304D;&#x6B8B;&#x308B;&#x305F;&#x3081;&#x306B;&#x9D8F;&#x306E;&#x80DA;&#x3092;&#x79FB;&#x690D;&#x3059;&#x308B;&#x3068;&#x751F;&#x4F53;&#x5185;&#x795E;&#x7D4C;&#x5824;&#x5178;&#x578B;&#x7684;&#x306A;&#x30C1;&#x30A7;&#x30FC;&#x30F3;&#x3092;&#x79FB;&#x884C;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057; ITSCs &#x5947;&#x5F62;&#x3067;&#x91CD;&#x75C7;&#x8907;&#x5408;&#x514D;&#x75AB;&#x4E0D;&#x5168;&#x30DE;&#x30A6;&#x30B9;&#x3092;&#x5F62;&#x6210;&#x3057;&#x307E;&#x305B;&#x3093;&#x3002;&#x6700;&#x5F8C;&#x306B;&#x3001;&#x6211;&#x3005; &#x306F;&#x78C1;&#x6C17;&#x7D30;&#x80DE;&#x306E;&#x4E26;&#x3079;&#x66FF;&#x3048;&#x306B;&#x57FA;&#x3065;&#x3044;&#x3066;&#x5206;&#x96E2;&#x6226;&#x7565;&#x958B;&#x767A; p75(NTR) &#x306E;&#x8CA0;&#x306E;&#x5927;&#x304D;&#x3044;&#x5E79;&#x7D30;&#x80DE;&#x3092;&#x5F62;&#x6210;&#x3057;&#x3001;p75(NTR) &#x3088;&#x308A;&#x901F;&#x304F;&#x5897;&#x6B96;&#x80AF;&#x5B9A;&#x7684;&#x306A; ITSCs ITSCs&#x3002;&#x4E00;&#x7DD2;&#x306B;&#x53D6;&#x3089;&#x308C;&#x3066;&#x6211;&#x3005; &#x306E;&#x7814;&#x7A76;&#x3001;&#x5C0F;&#x8AAC;&#x3001;&#x591A;&#x80FD;&#x6027;&#x3072;&#x3068; NCSCs &#x6F5C;&#x5728;&#x7684;&#x306A;&#x30BB;&#x30EB;&#x7F6E;&#x63DB;&#x7642;&#x6CD5;&#x306E;&#x305F;&#x3081;&#x306E;&#x5BB9;&#x6613;&#x306B;&#x30A2;&#x30AF;&#x30BB;&#x30B9;&#x53EF;&#x80FD;&#x306A;&#x30BD;&#x30FC;&#x30B9;&#x306B;&#x3064;&#x3044;&#x3066;&#x8AAC;&#x660E;&#x3057;&#x307E;&#x3059;&#x3002;

&#x65B0;&#x3057;&#x3044;&#x591A;&#x80FD;&#x6027;&#x795E;&#x7D4C;&#x5824;&#x7531;&#x6765;&#x5E79;&#x7D30;&#x80DE;&#x304B;&#x3089;&#x5927;&#x4EBA;&#x306E;&#x4EBA;&#x9593;&#x4E0B;&#x9F3B;&#x7532;&#x4ECB;&#x306E;&#x9694;&#x96E2;&#x3002;

&#xC778;&#xAC04;&#xC758; &#xC2E0;&#xACBD;&#xB3C4;&#xAC00; &#xBA38;&#xB9AC; &#xC720;&#xB798; &#xC904;&#xAE30; &#xC138;&#xD3EC; (NCSCs) &#xC7AC;&#xC0DD; &#xC758;&#xD559;&#xC5D0;&#xC11C;&#xC758; &#xD2B9;&#xBCC4; &#xD55C; &#xB192;&#xC740; &#xC18C;&#xC131; &#xBC0F; &#xC0AC;&#xC6A9;&#xC5D0; &#xB300; &#xD55C; &#xC720;&#xB9DD;&#xD55C; &#xD6C4;&#xBCF4;&#xC790;&#xB294;. &#xC5EC;&#xAE30;&#xC5D0; &#xC6B0;&#xB9AC;&#xAC00; &#xCC98;&#xC74C;&#xC73C;&#xB85C; &#xBE44; &#xC778;&#xAC04; &#xC131;&#xC778; &#xC5F4; &#xB4F1;&#xC758; &#xD638;&#xD761;&#xAE30; &#xC0C1;&#xD53C; &#xB0B4; &#xC18C;&#xC124; &#xC2E0;&#xACBD;&#xB3C4;&#xAC00; &#xBA38;&#xB9AC; &#xC720;&#xB798; &#xC904;&#xAE30; &#xC138;&#xD3EC; &#xC778;&#xAD6C; &#xC124;&#xBA85;. &#xC6B0;&#xC218; &#xD558; &#xACE0; &#xC911;&#xAC04; &#xC808; &#xB2EC;&#xB9AC; &#xC18C;&#xC2A4; &#xC7AC;&#xB8CC;&#xC758; &#xB192;&#xC740; &#xC591;&#xC758; &#xC778;&#xAC04;&#xC758; &#xC5F4; &#xB4F1; &#xD55C; &#xC808;&#xC5D0;&#xC11C; &#xACA9;&#xB9AC; &#xB41C; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xCD5C;&#xC18C; &#xCE68; &#xC2B5; &#xC218;&#xC220; &#xBC29;&#xBC95;&#xC774; &#xACA9;&#xB9AC;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; &#xB178;&#xC778; &#xD658;&#xC790;&#xC5D0;&#xB3C4; &#xD6A8;&#xC728;&#xC801;&#xC785;&#xB2C8;&#xB2E4;. &#xADF8;&#xB4E4;&#xC758; &#xB0B4; &#xD2C8;&#xC0C8; &#xC2DC;&#xC7A5; &#xB0B4;&#xC5D0;&#xC11C; &#xC5F4; &#xB4F1; &#xD55C; &#xBE44; &#xC904;&#xAE30; &#xC138;&#xD3EC; (ITSCs) nestin, p75(NTR), &#xBC0F; S100 &#xB192;&#xC740; &#xC218;&#xC900;&#xC758; &#xD45C;&#xD604;. &#xC548;&#xD2F0; p75 &#xD56D; &#xCCB4;&#xB97C; &#xC0AC;&#xC6A9; &#xD558; &#xC5EC; Immunoelectron &#xD604;&#xBBF8;&#xACBD; ITSCs &#xAD50; &#xAE30;&#xC6D0; Schwann &#xC138;&#xD3EC; nonmyelinating&#xC5D0; &#xBC00;&#xC811; &#xD558; &#xAC8C; &#xAD00;&#xB828; &#xD45C;&#xC2DC;. &#xC7AC;&#xBC30; ITSCs nestin s100&#xACFC; &#xC2E0;&#xACBD; &#xD06C;&#xB808;&#xC2A4;&#xD2B8; &#xB9C8;&#xCEE4; &#xC2AC;&#xB7EC;&#xADF8; &#xBC0F; sox10&#xC5D0; &#xB300; &#xD55C; &#xAE0D;&#xC815;&#xC801;&#xC778; &#xD588;&#xB2E4;. &#xC804;&#xCCB4; &#xAC8C;&#xB188; microarray &#xBD84;&#xC11D; WDR5, KLF4, &#xBC0F; c-MYC &#xD45C;&#xD604;&#xC758; &#xAC70;&#xC758; &#xBE44;&#xC2B7;&#xD55C; &#xBC18;&#xBA74; pluripotency &#xB9C8;&#xCEE4;&#xB85C; OCT4, SOX2, LIN28, &#xBC0F; NANOG, &#xC810;&#xC5D0;&#xC11C; &#xC778;&#xAC04;&#xC758; ES &#xC138;&#xD3EC;&#xC5D0; &#xB69C;&#xB837;&#xD55C; &#xCC28;&#xC774; &#xBCF4;&#xC600;&#xB2E4;. ITSCs &#xC2E0;&#xACBD; ectodermal &#xBC0F; mesodermal &#xD45C;&#xD604; &#xD615; &#xC138;&#xD3EC;&#xB85C; &#xBD84;&#xD654; &#xD560; &#xC218; &#xC788;&#xC5C8;&#xB2E4;. &#xB610;&#xD55C; ITSCs &#xC0DD;&#xC874;&#xACFC; &#xB2ED; &#xBC30;&#xC544;&#xC5D0; &#xC774;&#xC2DD; &#xB54C; vivo&#xC5D0;&#xC11C; &#xC2E0;&#xACBD; &#xD06C;&#xB808;&#xC2A4;&#xD2B8; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xCCB4;&#xC778; &#xB9C8;&#xC774;&#xADF8;&#xB808;&#xC774;&#xC158;&#xC744; &#xC218;&#xD589;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; ITSCs &#xC2EC;&#xD55C; &#xACB0;&#xD569;&#xB41C; immunodeficient &#xC950;&#xC5D0; teratomas&#xB97C; &#xD615;&#xC131; &#xD558;&#xC9C0; &#xC54A;&#xC2B5;&#xB2C8;&#xB2E4;. &#xB9C8;&#xC9C0;&#xB9C9;&#xC73C;&#xB85C;, &#xC6B0;&#xB9AC;&#xAC00; &#xC790;&#xAE30; &#xC138;&#xD3EC; &#xBD84;&#xB958;&#xC5D0; &#xB530;&#xB77C; &#xBD84;&#xB9AC; &#xC804;&#xB7B5; &#xAC1C;&#xBC1C; p75(ntr)&#xC758; &#xD070; neurospheres&#xC744; &#xD615;&#xC131; &#xD558; &#xACE0; p75(NTR) &#xBCF4;&#xB2E4; &#xBE60;&#xB974;&#xAC8C; &#xD655;&#xC0B0; &#xD558;&#xB294; &#xAE0D;&#xC815;&#xC801;&#xC778; ITSCs ITSCs &#xBD80;&#xC815;. &#xD568;&#xAED8; &#xCC0D;&#xC740; &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; &#xC18C;&#xC124;, &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC138;&#xD3EC; &#xB300;&#xCCB4; &#xC694;&#xBC95; multipotent &#xC778;&#xAC04; Ncscs&#xC758; &#xC27D;&#xAC8C; &#xC561;&#xC138;&#xC2A4;&#xD560; &#xC218; &#xC788;&#xB294; &#xC18C;&#xC2A4;&#xB97C; &#xC124;&#xBA85; &#xD569;&#xB2C8;&#xB2E4;.

&#xC18C;&#xC124; multipotent &#xC2E0;&#xACBD;&#xB3C4;&#xAC00; &#xBA38;&#xB9AC; &#xC720;&#xB798; &#xC904;&#xAE30; &#xC138;&#xD3EC;&#xC758; &#xC131;&#xC778; &#xC778;&#xAC04;&#xC758; &#xC5F4; &#xB4F1; &#xBE44;&#xC5D0;&#xC11C; &#xACA9;&#xB9AC;.

Humanas derivados de la cresta neural c&eacute;lulas madre adultas (NCSCs) son de extraordinaria alta plasticidad y candidatos prometedores para el uso en medicina regenerativa. Aqu&iacute; describimos por primera vez a una poblaci&oacute;n de nuevos derivados de la cresta neural de la c&eacute;lula de v&aacute;stago dentro del epitelio respiratorio del humano adulto inferior cornete nasal. En contraste con los cornetes superior y medio, grandes cantidades de material de origen podr&iacute;an ser aislados de humanos cornetes inferiores. Utilizando m&eacute;todos aislamiento de cirug&iacute;a m&iacute;nimamente invasiva es eficaz incluso en pacientes de edad avanzada. Dentro de su nicho end&oacute;geno, c&eacute;lulas cornetes inferiores (ITSCs) expresaron altos niveles de nestina, p75(NTR) y S100. La microscopia de immunoelectron usando los anticuerpos anti-p75 muestra que ITSCs son de origen glial y estrechamente vinculado a nonmyelinating las c&eacute;lulas de Schwann. ITSCs cultivadas eran positivas para nestina y S100 y los marcadores de la cresta neural Slug y SOX10. An&aacute;lisis de microarrays de genoma entero mostraron diferencias pronunciadas a c&eacute;lulas madre embrionarias humanas con respecto a los marcadores de pluripotencia OCT4, SOX2, LIN28 y NANOG, mientras que la expresi&oacute;n de WDR5, KLF4 y c-MYC fue casi similar. ITSCs fueron capaces de diferenciarse en c&eacute;lulas con fenotipo neuro-ectod&eacute;rmico y mesod&eacute;rmico. Adem&aacute;s ITSCs son capaces de sobrevivir y realizar cresta neural cadena t&iacute;pica migraci&oacute;n en vivo cuando trasplant&oacute; en embriones de pollo. Sin embargo ITSCs no forman los teratomas en ratones inmunodeficientes combinados severos. Finalmente, desarrollamos una estrategia de separaci&oacute;n basada en la separaci&oacute;n magn&eacute;tica celular de p75(NTR) positivas ITSCs que formaron grandes neuroesferas y proliferaban m&aacute;s r&aacute;pido que p75(NTR) negativo ITSCs. Tomados en conjunto nuestro estudio describe una novela, la fuente accesible de NCSCs humanas pluripotentes para terapia de reemplazo celular potencial.

Aislamiento de las novela multipotentes derivados de la cresta neural c&eacute;lulas madre de adultos cornete nasal humano inferior.

Cognitive decline during aging is correlated with a continuous loss of cells within the brain and especially within the hippocampus, which could be regenerated by adult neurogenesis. Here we show that genetic ablation of NF-κB resulted in severe defects in the neurogenic region (dentate gyrus) of the hippocampus. Despite increased stem cell proliferation, axogenesis, synaptogenesis and neuroprotection were hampered, leading to disruption of the mossy fiber pathway and to atrophy of the dentate gyrus during aging. Here, NF-κB controls the transcription of FOXO1 and PKA, regulating axogenesis. Structural defects culminated in behavioral impairments in pattern separation. Re-activation of NF-κB resulted in integration of newborn neurons, finally to regeneration of the dentate gyrus, accompanied by a complete recovery of structural and behavioral defects. These data identify NF-κB as a crucial regulator of dentate gyrus tissue homeostasis suggesting NF-κB to be a therapeutic target for treating cognitive and mood disorders.

Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus.

Schwann cells (SCs) are the supporting cells of the peripheral nervous system and originate from the neural crest. They play a unique role in the regeneration of injured peripheral nerves and have themselves a highly unstable phenotype as demonstrated by their unexpectedly broad differentiation potential. Thus, SCs can be considered as dormant, multipotent neural crest-derived progenitors or stem cells. Upon injury they de-differentiate via cellular reprogramming, re-enter the cell cycle and participate in the regeneration of the nerve. Here we describe a protocol for efficient generation of neurospheres from intact adult rat and murine sciatic nerve without the need of experimental in vivo pre-degeneration of the nerve prior to Schwann cell isolation. After isolation and removal of the connective tissue, the nerves are initially plated on poly-D-lysine coated cell culture plates followed by migration of the cells up to 80% confluence and a subsequent switch to serum-free medium leading to formation of multipotent neurospheres. In this context, migration of SCs from the isolated nerve, followed by serum-free cultivation of isolated SCs as neurospheres mimics the injury and reprograms fully differentiated SCs into a multipotent, neural crest-derived stem cell phenotype. This protocol allows reproducible generation of multipotent Schwann cell-derived neurospheres from sciatic nerve through cellular reprogramming by culture, potentially marking a starting point for future detailed investigations of the de-differentiation process.

Generation of Schwann cell-derived multipotent neurospheres isolated from intact sciatic nerve.

The identification of the mutation causing the phenotype of the amyotrophic lateral sclerosis (ALS) model mouse, wobbler, has linked motor neuron degeneration with retrograde vesicle traffic. The wobbler mutation affects protein stability of Vps54, a ubiquitously expressed vesicle-tethering factor and leads to partial loss of Vps54 function. Moreover, the Vps54 null mutation causes embryonic lethality, which is associated with extensive membrane blebbing in the neural tube and is most likely a consequence of impaired vesicle transport. Investigation of cells derived from wobbler and Vps54 null mutant embryos demonstrates impaired retrograde transport of the Cholera-toxin B subunit to the trans-Golgi network and mis-sorting of mannose-6-phosphate receptors and cargo proteins dependent on retrograde vesicle transport. Endocytosis assays demonstrate no difference between wobbler and wild type cells, indicating that the retrograde vesicle traffic to the trans-Golgi network, but not endocytosis, is affected in Vps54 mutant cells. The results obtained on wobbler cells were extended to test the use of cultured skin fibroblasts from human ALS patients to investigate the retrograde vesicle traffic. Analysis of skin fibroblasts of ALS patients will support the investigation of the critical role of the retrograde vesicle transport in ALS pathogenesis and might yield a diagnostic prospect.

Loss of vps54 function leads to vesicle traffic impairment, protein mis-sorting and embryonic lethality.

In human globozoospermia, round-headed spermatozoa lack an acrosome and therefore cannot properly interact with oocytes. In the wobbler (WR) mouse, an L967Q missense mutation in the vesicular protein-sorting factor VPS54 causes motor neuron degeneration and globozoospermia. Although electron microscopy of WR testis shows all major components of spermatogenesis, they appear in a deranged morphology that prevents the formation of the acrosome. In order to determine proteome-wide changes, affected testes were analysed by 2D-DIGE and MS. The concentration of 8 proteins was increased and that of 35 proteins decreased as compared to wild type. Mass spectrometric analysis identified proteins with an altered concentration to be associated with metabolite transport, fatty acid metabolism, cellular interactions, microtubule assembly and stress response (chaperones Hsp70-2 and Hsp90α). Minor changes were observed for proteins involved in cell redox homeostasis, cytoskeleton formation, PTMs, detoxification and metabolism. The most dramatically decreased protein in WR testis was identified as fatty acid binding protein FABP3, as confirmed by immunoblot analysis. We conclude that a missense mutation in VPS54, an essential component of the Golgi-associated retrograde protein complex, not only prevents the formation of an acrosome but also initiates a cascade of metabolic abnormalities and a stress reaction.

Article	Year
Progressive loss of striatal neurons causes motor dysfunction in MND2 mutant mice and is not prevented by Bcl-2. Experimental neurology\| PubMed ID: 12009762	2002
Acute pathophysiological effects of muscle-expressed Dp71 transgene on normal and dystrophic mouse muscle. Journal of applied physiology (Bethesda, Md. : 1985)\| PubMed ID: 14555666	2003
Elimination by necrosis, not apoptosis, of embryonic extraocular muscles in the muscular dysgenesis mutant of the mouse. Cell and tissue research\| PubMed ID: 14618389	2004
The structural examination of myocardial samples from patients with end-stage heart failure supported by ventricular assist devices using electron microscopy and amino acid analysis reveals ... The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation\| PubMed ID: 15063398	2004
Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nature genetics\| PubMed ID: 16244655	2005
Panel 2.9: repair and recovery of health systems. Prehospital and disaster medicine\| PubMed ID: 16496629	2005
EHTP: improving health quality through health technology. Conference proceedings : ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference\| PubMed ID: 17959465	2006
Endosomal accumulation of APP in wobbler motor neurons reflects impaired vesicle trafficking: implications for human motor neuron disease. BMC neuroscience\| PubMed ID: 21385376	2011
Schwann cells can be reprogrammed to multipotency by culture. Stem cells and development\| PubMed ID: 21466279	2011
Isolation of novel multipotent neural crest-derived stem cells from adult human inferior turbinate. Stem cells and development\| PubMed ID: 22128806	2012
Regrowing the adult brain: NF-κB controls functional circuit formation and tissue homeostasis in the dentate gyrus. PloS one\| PubMed ID: 22312433	2012
Generation of Schwann cell-derived multipotent neurospheres isolated from intact sciatic nerve. Stem cell reviews\| PubMed ID: 22664741	2012
Loss of vps54 function leads to vesicle traffic impairment, protein mis-sorting and embryonic lethality. International journal of molecular sciences\| PubMed ID: 23708095	2013
Pathoproteomics of testicular tissue deficient in the GARP component VPS54: The wobbler mouse model of globozoospermia. Proteomics\| PubMed ID: 24115398	2013

Peter Heimann

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