Results - Details
Search command : Author="Μαυροθαλασσίτης"
And Author="Γεώργιος"
Current Record: 7 of 26
|
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 |
|
Ανάπτυξη κρανιοπροσωπικού συμπλέγματος |
|
Κρανιακές ραφές |
|
Μεσεγχυματικά βλαστικά κύτταρα |
|
Οστεογένεση |
|
Ρετινοϊκό οξύ |
Issue date |
2021-07-30 |
Collection
|
School/Department--School of Medicine--Department of Medicine--Doctoral theses
|
|
Type of Work--Doctoral theses
|
Permanent Link |
https://elocus.lib.uoc.gr//dlib/e/5/a/metadata-dlib-1625139259-137281-11133.tkl
|
Views |
535 |