Abstract not available

Estrogen-receptor-related receptor gamma, ERRγ, is highly expressed in cartilage and upregulates the chondrogenic transcription factor, Sox9, in a chondrocytic cell line. To assess the effect of increasing ERRγ activity on cartilage in vivo, we generated transgenic animals driving ERRγ expression with a chondrocyte-specific promoter. I verified that one transgenic line exhibited 26% increased ERRγ protein at E14.5. No major morphological defects were seen at this stage, but I observed significant reduction in the size of the appendicular skeleton in P7 mice, such that all elements of the appendicular skeleton were significantly reduced by 4 – 10%. I continued the phenotype analysis at the histological level and found that the P7 animals displayed significantly reduced growth plate height, caused by deficiencies in the size of the proliferative and hypertrophic zones of the growth plate. This suggests a previously unknown role for ERRγ in regulating endochondral ossification in growth plate chondrocytes.

Estrogen-receptor-related receptor gamma, ERRγ, is highly expressed in cartilage and upregulates the chondrogenic transcription factor, Sox9, in a chondrocytic cell line. To assess the effect of increasing ERRγ activity on cartilage in vivo, we generated transgenic animals driving ERRγ expression with a chondrocyte-specific promoter. I verified that one transgenic line exhibited 26% increased ERRγ protein at E14.5. No major morphological defects were seen at this stage, but I observed significant reduction in the size of the appendicular skeleton in P7 mice, such that all elements of the appendicular skeleton were significantly reduced by 4 – 10%. I continued the phenotype analysis at the histological level and found that the P7 animals displayed significantly reduced growth plate height, caused by deficiencies in the size of the proliferative and hypertrophic zones of the growth plate. This suggests a previously unknown role for ERRγ in regulating endochondral ossification in growth plate chondrocytes.

Den här uppsatsens syfte har varit att kartlägga skillnader i representation av individer med dvärgväxt, från antikens Egypten fram till renässansen. Forskning har gjorts på detta utanför Sverige, men de fyra svenska människorna med dvärgväxt har inte tillfogats och jämförts med det utländska materialet innan denna uppsats. Metoden har varit en litterär jämförelse där andra författare har analyserats. De förhistoriska och historiska litterära verken som dessa författare undersökt har bland annat innefattat egyptiska papyrus, grekisk och romersk lagstiftning och medeltida dokument. Konst från dessa tider har också undersökts. Resultatet av uppsatsen har varit att uppfattningen av dvärgväxt har undergått stor variation genom förhistorien och historien. Ju längre tillbaka vi går desto högre tolerans finner vi. Dvärgar var populära i Egypten på ett sätt som återkommer i medeltidens och renässansens Europa, då hovdvärgar är på modet. Hur det har sett ut i Skandinavien är svårt att säga trots de mänskliga kvarlevorna som påträffats av individer med dvärgväxt. I uppsatsen tas även myter och folklore om dvärgar upp för att måla en djupare förståelsebild av acceptansen i samhället och hur legender kan antingen hjälpa eller stjälpa i sammanhanget.

Thesis (doctoral)--Universität Jena, 1934. / At head of title: Aus dem zahnärtzlichen Institut der Universität Jena. "Lebenslauf": p. 34.

Thesis (doctoral)--Universität Jena, 1934. / At head of title: Aus dem zahnärtzlichen Institut der Universität Jena. "Lebenslauf": p. 34.

Mutations in the COL10A1 gene cause metaphyseal chondrodysplasia type Schmid (MCDS) by triggering ER stress and unfolded protein response (UPR). MCDS is characterised by a mild short-limb dwarfism accompanied by expansion of the cartilage growth plate hypertrophic zone (HZ) and altered differentiation of hypertrophic chondrocytes (HCs). ATF6 is one of the UPR mediators, which exists in two isoforms, ATF6α and ATF6β. Activation and up-regulation of ATF6α was a prominent biochemical sign of ER stress in a mouse model of MCDS, COL10a1 p.N617K. Although ATF6β is induced and activated in response to ER stress in a similar fashion to ATF6α, the role and significance of ATF6β in the pathology of many ER stress-associated diseases including MCDS is unknown. Here we utilized a combination of in vitro and in vivo approaches to define the precise role of each isoform of ATF6 in MCDS.To investigate the functions of ATF6α and ATF6β in vitro, we developed a MCDS cell model system (expressing either the wild type collagen X or one of the following MCDS-causing mutant forms of the protein: p.N617K, G618V, Y598D, and NC1del10) in which the expression of either ATF6α or ATF6β was efficiently silenced using siRNAs. ATF6α knockdown in HeLa cells expressing different MCDS-causing mutations suppressed the increased expression of UPR-associated genes such as BiP leading to an elevated ER stress, based on increased XBP1 splicing and/or ATF4 protein. In contrast, ATF6β knockdown did not significantly affect the mutant collagen X-induced increased expression of UPR-associated genes. Furthermore, the ER stress levels were significantly reduced in the ATF6β knockdown MCDS mutant cells based on the lower levels of XBP1 splicing and/or ATF4 protein detected. We then crossed the ATF6α/β knockout mice models with COL10a1 p.N617K mouse model of MCDS to investigate the function of ATF6α and ATF6β in vivo. Ablation of ATF6α in MCDS mice further- reduced the endochondral bone growth rate, further expanded the growth plate hypertrophic zone, and disrupted differentiation of HCs. Therefore, ATF6α appeared to play a chondroprotective role in MCDS as its deficiency caused an increase in the severity of the disease. Of particular note, the level of ER stress was further increased in the absence of ATF6α in MCDS, based on enhanced activities of PERK and IRE1 signalling pathways in compensation for the ATF6α loss. Paradoxically, ablation of ATF6β in MCDS mice reduced the intracellular retention of collagen X protein, and alleviated the ER stress as judged by the attenuated activities of PERK and IRE1 signalling pathways. The reduced ER stress resulting from deficiency for ATF6β in MCDS mice restored the expression of collagen X mRNA towards normal and improved the differentiation of HCs, causing a mark decrease in the expansion of HZ. The results presented within this thesis greatly increased our understanding of the function of ATF6α and ATF6β and their interplay in the pathogenesis of MCDS. We demonstrated an indispensable beneficiary role for ATF6α but a detrimental role for its closely related isoform, ATF6β, in pathology of MCDS. We also showed that the role of ATF6β should not be ignored. These findings may be used to develop a potential therapeutic strategy for MCDS through targeting and enhancing ATF6α-dependent and/or attenuating/blocking of ATF6β-dependent signalling pathways.

Introduction: Achondroplasia is the most common bone dysplasia. It is caused by mutations in the FGFR3 gene, which is involved in regulation of proliferation and maturation of chondrocytes on the growth plates. Activating mutation results in impaired endochondral ossification and a wide range of symptoms: severe growth disorder with limb shortening, macrocephaly with risk of hydrocephalus, mid-facial dysplasia, sleep apnea, narrowing of the spinal canal, increased risk of respiratory complications, and airway inflammation. The current rapid technological development has led to a better understanding of the processes of epiphyseal growth cartilage, thus enabling the development of new drugs for the treatment of this disorder (modified CNP, soluble FGFR3, meclozine). Nevertheless, current treatment is primarily symptomatic. It is very important to have a growth patterns of patients with achondroplasia who have not been affected by any growth promoting treatment (prolongation surgery, growth hormone). Objectives: The aim of this study is to evaluate the growth of Czech patients with achondroplasia, to compare our data with the world-wide used data by Horton et al. (1978) and the current data by del Pino et al. (2018). The next aim was to verify the accuracy of the multiplier method of final height...

Die menschliche Entwicklung ist charakterisiert durch ein rasches fetales Wachstum, ein langsames postnatales Wachstum, ein kontinuierliches Wachstum im Laufe der Kindheit sowie einen Wachstumsschub während der Pubertät. In den letzten Jahren wurde gezeigt, dass Mutationen in den Genen des Pericentrins (PCNT) und des Insulin-like growth factor-1 Rezeptors (Insulin ähnlicher Wachstumsfaktor Typ 1 Rezeptor, IGF1R) seltene Auslöser von prä- und postnataler Wachstumsrestriktion darstellen können. In dieser Arbeit wird eine stark wachstumsretardierte Patientin mit zusammengesetzter heterozygoter PCNT-Mutation und heterozygoter IGF1R-Mutation beschrieben. Ziel dieser Arbeit war zum einen die ausführliche klinische Charakterisierung der Patientin. Zum anderen sollte auf zellulärer Ebene überprüft werden, inwieweit die genannten Mutationen den Phänotyp der Patientin erklären. Um die funktionellen Zusammenhänge zu untersuchen, wurden in vitro Assays durchgeführt. Hierfür standen neben mit dem mutierten Rezeptor transfizierte IGF1R-defiziente Mausfibroblasten (R--Zellen) auch humane Fibroblasten zur Verfügung. Es wurden die totale und die extrazelluläre Rezeptorexpression, die IGF1 induzierte Stimulierung und die Signaltransduktion des mutierten IGF1R untersucht. Weiterhin wurde die proliferative Kapazität der Patientenfibroblasten analysiert. Die Ergebnisse dieser Analysen ergaben keine relevanten Funktionseinschränkungen des mutierten IGF1R. Demgegenüber steht eine reduzierte Zellproliferation der Patientenfibroblasten. Die zugrunde liegenden Mechanismen der verminderten Proliferationskapazität sind womöglich den PCNT-Mutationen zuzurechnen. In Versuchen zur IGF1 induzierten Proliferationssteigerung konnte die Proliferation der Patientenfibroblasten zwar kurzfristig stimuliert werden, bei längerer IGF1-Stimulation konnte jedoch das bestehende Proliferationsdefizit nicht ausgeglichen werden. Die genauen molekularbiologischen Auswirkungen der PCNT-Mutation in Bezug auf den ausgeprägten Phänotyp der Patientin müssen in zukünftigen Arbeiten noch weiter aufgeklärt werden.

The San Luis Valley is a large valley formation in Colorado surrounded on either side by mountain ranges exceeding 4,267 m. Within the Valley, two of the 14 amphibian and reptile species are dwarfed: the short-horned lizard (Phrynosoma hernandesi) and the Great Plains toad (Anaxyrus cognatus). Since its initial reporting in 1968 and confirmation in 1981, no research further investigating this dwarfism has been conducted. I collected morphological measurements to determine the extent and patterns of dwarfism of both species. I then investigated the genetics of both species using mitochondrial DNA to determine whether they are genetically distinct, their colonization histories within the Valley, and whether the Valley functions as a reproductive barrier. Lastly, I report life/natural-history data to determine the effects of dwarfism. Phrynosoma hernandesi and A. cognatus were significantly dwarfed and showed an increase in sexual size dimorphism compared to populations surrounding the Valley. Valley populations of P. hernandesi show high amounts of genetic divergence from populations surrounding the Valley while A. cognatus shows minimal genetic variation throughout its range. Based on the variable distribution of genetic variation in the Valley, historic climate patterns, and fossil records, there are two most likely colonization histories for P. hernandesi: 1.) populations colonized the Valley during a singular event and have since diverged or 2.) populations colonized the Valley during two events that correlate with the two warm, dry periods within the last 0.8 MYA. Dwarfed P. hernandesi consumed diets similar to populations outside the Valley although there is local variation in the diversity of prey items consumed. Phrynosoma hernandesi at Zapata Ranch showed annual variation in body size and morphology while population dynamics correlate with the timing of precipitation. Also, females show a reduced reproductive output, producing fewer neonates but of equal size to non-dwarfed neonates. Collectively, findings from this study suggest that Valley populations represent unique taxa and should be considered for further genetic study to determine their taxonomic and conservation status.