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Identifier

000440957

Title

Study of the mechanism underlying premature suture closure in the animal model of ERF-related craniosynostosis

Alternative Title

Μελέτη του μηχανισμού που οδηγεί στην πρόωρη σύντηξη των ραφών στο ζωικό μοντέλο της σχετιζόμενης με τον ERF κρανιοσυνοστέωσης

Author

Βογιατζή, Αγγελική

Thesis advisor

Μαυροθαλασσίτης, Γεώργιος

Reviewer

Καρδάσης, Δημήτριος
Χαλεπάκης , Γεώργιος

Abstract

The formation of the human head is a complex process involving sequences of crosstalk events between different germ layers and tissues and spatiotemporal activation of a variety of molecular signaling cascades. Cranial sutures comprise the connective tissues between the bony elements of skull and have a critical role in the development and growth of the calvarial bones. Non committed mesenchymal stem cells are found to reside in the suture mesenchyme that once enter the intramembranous ossification pathway give rise to proliferating populations of osteoprogenitor and preosteoblast cells that eventually appose osteoblasts at the edges of the developing bones. Resorption and bone reshaping takes place by osteoclasts later too. The balance between all these populations of cells seems to be crucial for the suture patency and consequently for the coordination of skull and brain development. Distortion of this balance can lead to the premature closure of one or more of the cranial sutures, a condition termed craniosynostosis, with an occurrence rate of approximately one in 2500 births, that results in abnormal head shapes along with vision, hearing and mental impairment unless treated. During the last decades, considerable amount of effort has been put into the identification of the mechanisms that lead to the appearance of the phenotype. However, the presence of multiple cell populations in sutures, the lack of specific cellular markers and the difficulties in the isolation of suture stem cells, hinder such efforts. Haploinsufficiency of the ETS-DNA binding transcriptional repressor factor ERF causes premature suture closure in humans and in ErfLoxP/- mice expressing only 29% of the normal Erf protein levels. Like humans, ErfLoxP/- mice display facial dysmorphism with no other obvious skeletal defects beyond synostosis which is preceded by a reduction in the ossification of calvarial bones at the onset of postnatal life. In previous studies ERF has been shown to regulate cellular proliferation downstream of ERK1/2 signalling along with differentiation processes with particular respect to trophoblast stem cell and erythroid differentiation. There were no reports however, about its role in either bone formation or craniofacial development. The aim of the current study was to provide an understanding of the mechanisms underlying the emergence of ERF-associated craniosynostosis phenotype, often characterised as insidious due to its high complexity. In the present study, we established in vitro cultures of primary suture-derived cells and developed selective conditions for the expansion of a mesenchymal stem/ progenitor cell population from suture explants to study the role of Erf in cranial suture fate and intramembranous skull ossification. By performing ex vivo cellular assays and transcriptomic analysis we provide evidence that Erf is required for the initial commitment of suture mesenchymal stem/ progenitor cells towards the osteogenic lineage, while at a later stage seems to be also essential for the maintenance of committed proliferating progenitor cells undergoing differentiation. Our data indicate that Erf affects the commitment and differentiation of cranial suture mesenchymal stem/ progenitor cells via the retinoic acid (RA) pathway. Decreased levels of Erf lead to increased expression of Cyp26b1 gene, encoding the RAcatabolizing enzyme, resulting in sustained proliferation and decreased mesenchymal stem cell differentiation. Exogenous addition of retinoic acid rescues the osteogenesis defect of Erf-insufficient (ErfLoxP/-) cells. The abnormal mineralization of the calvarial bones may be attributed to the distortion in retinoic acid concentration gradient during skull development. Further studies would be necessary to explore the spatiotemporal function of Erf and its effect on RA concentration gradients in cranial bone and suture development. Pharmacological enhancement of nuclear Erf action as well as retinoic acid level modulation hold promise for the treatment of craniosynostosis and reassert that continuous ERF presence is required for normal craniofacial development

Language

English, Greek

Subject

Cranial sutures

Craniofacial development

ETS2-repressor factor (ERF)

ETS2-καταστολέας(ERF)

Mesenchymal stem cells

Osteogenesis

Retinoic acid

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