A PDGFRalpha perspective on PDGF signalling in developmental and pathological processes
Author: Gallini, Radiosa
Date: 2014-12-05
Location: Johnsalen, Tomtebodavägen 18 A, Karolinska Institutet, Solna
Time: 10.15
Department: Inst för medicinsk biokemi och biofysik / Dept of Medical Biochemistry and Biophysics
View/ Open:
Thesis (13.68Mb)
Abstract
Platelet-derived growth factors PDGFs are a family of ligands and receptors that regulate
multiple processes of paramount importance during embryonic development. They are also
involved in several pathological events, spanning from tumours to fibrotic diseases. PDGFs have
been studied for more than 30 years, but the mechanisms, as well as the tissue and cell type
specific physiological roles of PDGF biology are still not fully understood.
The work presented in this thesis investigates the role of PDGFR-alpha in cell differentiation during cardiac tissue specification, and the effects of PDGF overexpression in the myocardium during development and in the context of cardiac injury. We also examine the elusive function of the PDGF-A retention motif in PDGFR-alpha signalling during morphogenesis. The adoption of a reporter construct knocked into the PDGFR-alpha locus allowed us to precisely follow its site of expression.
Here we report evidence of a role for PDGFR-alpha signalling in the recruitment and differentiation of second heart field-derived cells during cardiac inflow tract development (paper I).
We also studied of the physiological role of the PDGF-A retention motif and the effects of its ablation. This work points to a preponderant role for the diffusible isoform in PDGFR-alpha signalling (paper II).
The data presented in paper III investigate the effects of PDGF-A and PDGF-B overexpression in the developing mouse myocardium, and complements previously published reports on PDGF-C and PDGF-D overexpression in the same system. Our findings extend the evaluation of the role of PDGFs in myocardial fibrosis induction, and suggest PDGFR-alpha positive cells as the source of excessive extracellular matrix deposition in the heart in response to ectopic PDGF expression.
Ectopic expression of the different PDGF ligands in injured and inflamed cardiac tissue reveals an unexpected role for PDGFs in tissue recovery, that appears to be mediated by PDGFR-alpha signalling cells (paper IV).
Many questions remain open-ended regarding PDGF signalling. The work presented in this thesis points at new and interesting directions for future studies.
The work presented in this thesis investigates the role of PDGFR-alpha in cell differentiation during cardiac tissue specification, and the effects of PDGF overexpression in the myocardium during development and in the context of cardiac injury. We also examine the elusive function of the PDGF-A retention motif in PDGFR-alpha signalling during morphogenesis. The adoption of a reporter construct knocked into the PDGFR-alpha locus allowed us to precisely follow its site of expression.
Here we report evidence of a role for PDGFR-alpha signalling in the recruitment and differentiation of second heart field-derived cells during cardiac inflow tract development (paper I).
We also studied of the physiological role of the PDGF-A retention motif and the effects of its ablation. This work points to a preponderant role for the diffusible isoform in PDGFR-alpha signalling (paper II).
The data presented in paper III investigate the effects of PDGF-A and PDGF-B overexpression in the developing mouse myocardium, and complements previously published reports on PDGF-C and PDGF-D overexpression in the same system. Our findings extend the evaluation of the role of PDGFs in myocardial fibrosis induction, and suggest PDGFR-alpha positive cells as the source of excessive extracellular matrix deposition in the heart in response to ectopic PDGF expression.
Ectopic expression of the different PDGF ligands in injured and inflamed cardiac tissue reveals an unexpected role for PDGFs in tissue recovery, that appears to be mediated by PDGFR-alpha signalling cells (paper IV).
Many questions remain open-ended regarding PDGF signalling. The work presented in this thesis points at new and interesting directions for future studies.
List of papers:
I. Cardiac malformations in PDGFR-alpha mutant embryos are associated with increased expression of WT1 and Nkx 2.5 in the second heart field. Noortje A. M. Bax, Steven B. Bleyl, Radiosa Gallini, Lambertus J. Wisse, Jennifer Hunter, Angelique A. M. Van Oorschot, Edris A. F. Mahtab, Heleen Lie-Venema, Marie-Jose Goumans, Christer Betsholtz, Adriana C. Gittenbergerde Groot (2010). Developmental dynamics 239: 2307-2317
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Analysis of mice lacking the heparin-binding splice isoform of platelet-derived growth factor A. Johanna Andrae, Hans Ehrencrona, Radiosa Gallini, Mark Lal, Hao Ding, Christer Betsholtz (2013). Molecular and cellular biology 33: 4030-4040
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Isoform specific modulation of inflammation induced by adenoviral mediated delivery of PDGF in the adult heart. Radiosa Gallini, Jenni Huusko, Seppo Ylä-Herttuala, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]
IV. PDGFR-alpha positive cells in PDGF-A and PDGF-B induced cardiac fibrosis in mouse. Radiosa Gallini, Per Lindblom, Cecilia Bondjers, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]
I. Cardiac malformations in PDGFR-alpha mutant embryos are associated with increased expression of WT1 and Nkx 2.5 in the second heart field. Noortje A. M. Bax, Steven B. Bleyl, Radiosa Gallini, Lambertus J. Wisse, Jennifer Hunter, Angelique A. M. Van Oorschot, Edris A. F. Mahtab, Heleen Lie-Venema, Marie-Jose Goumans, Christer Betsholtz, Adriana C. Gittenbergerde Groot (2010). Developmental dynamics 239: 2307-2317
Fulltext (DOI)
Pubmed
View record in Web of Science®
II. Analysis of mice lacking the heparin-binding splice isoform of platelet-derived growth factor A. Johanna Andrae, Hans Ehrencrona, Radiosa Gallini, Mark Lal, Hao Ding, Christer Betsholtz (2013). Molecular and cellular biology 33: 4030-4040
Fulltext (DOI)
Pubmed
View record in Web of Science®
III. Isoform specific modulation of inflammation induced by adenoviral mediated delivery of PDGF in the adult heart. Radiosa Gallini, Jenni Huusko, Seppo Ylä-Herttuala, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]
IV. PDGFR-alpha positive cells in PDGF-A and PDGF-B induced cardiac fibrosis in mouse. Radiosa Gallini, Per Lindblom, Cecilia Bondjers, Christer Betsholtz, Johanna Andrae (2014). [Manuscript]
Institution: Karolinska Institutet
Supervisor: Betsholtz, Christer
Issue date: 2014-11-14
Rights:
Publication year: 2014
ISBN: 978-91-7549-740-2
Statistics
Total Visits
Views | |
---|---|
A ...(legacy) | 850 |
A ... | 346 |
Total Visits Per Month
March 2024 | April 2024 | May 2024 | June 2024 | July 2024 | August 2024 | September 2024 | |
---|---|---|---|---|---|---|---|
A ... | 0 | 1 | 1 | 2 | 2 | 4 | 3 |
File Visits
Views | |
---|---|
Thesis_Radiosa_Gallini.pdf(legacy) | 267 |
Thesis_Radiosa_Gallini.pdf | 250 |
Radiosa Gallini.pdf(legacy) | 6 |
license.txt(legacy) | 1 |
Top country views
Views | |
---|---|
China | 372 |
Germany | 258 |
United States | 224 |
Sweden | 95 |
South Korea | 16 |
Ireland | 13 |
France | 11 |
Russia | 8 |
Switzerland | 6 |
Finland | 6 |
Top cities views
Views | |
---|---|
Shenzhen | 241 |
Ashburn | 56 |
Kiez | 45 |
Stockholm | 31 |
Beijing | 24 |
Mercer Island | 16 |
Sunnyvale | 14 |
Dublin | 13 |
Seoul | 12 |
Nürnberg | 10 |