D'Aniello, Cristina
(2010)
Identification and functional characterization of the G-protein coupled receptor APJ and its ligand apelin in embryonic stem cells: a novel pathway regulating mammalian cardiomyogenesis.
[Tesi di dottorato]
(Inedito)
| Tipologia del documento: |
Tesi di dottorato
|
| Lingua: |
English |
| Titolo: |
Identification and functional characterization of the G-protein coupled receptor APJ and its ligand apelin in embryonic stem cells: a novel pathway regulating mammalian cardiomyogenesis |
| Autori: |
| Autore | Email |
|---|
| D'Aniello, Cristina | daniello@igb.cnr.it |
|
| Data: |
29 Novembre 2010 |
| Numero di pagine: |
60 |
| Istituzione: |
Università degli Studi di Napoli Federico II |
| Dipartimento: |
Biologia e patologia cellullare e molecolare "L. Califano" |
| Scuola di dottorato: |
Medicina molecolare |
| Dottorato: |
Genetica e medicina molecolare |
| Ciclo di dottorato: |
23 |
| Coordinatore del Corso di dottorato: |
| nome | email |
|---|
| Nitsch, Lucio | nitsch@unina.it |
|
| Tutor: |
| nome | email |
|---|
| Minchiotti, Gabriella | minchiotti@igb.cnr.it |
|
| Data: |
29 Novembre 2010 |
| Numero di pagine: |
60 |
| Parole chiave: |
embryonic stem cells; cardiomyogenesis; cripto; apelin; APJ/msrl |
| Settori scientifico-disciplinari del MIUR: |
Area 06 - Scienze mediche > MED/03 - Genetica medica
Area 05 - Scienze biologiche > BIO/18 - Genetica |
[error in script]
[error in script]
| Depositato il: |
13 Dic 2010 22:31 |
| Ultima modifica: |
30 Apr 2014 19:44 |
| URI: |
http://www.fedoa.unina.it/id/eprint/8148 |
| DOI: |
10.6092/UNINA/FEDOA/8148 |
Abstract
The commitment of mesodermal precursors to a cardiac fate is one of the first
events in embryogenesis. It results from inductive interactions occurring during
gastrulation in a temporally and spatially regulated manner. Embryonic Stem
Cells (ESCs) are a powerful tool to study the early events of cardiac lineage
specification in mammals; in particular, several cardiac cell populations have
been generated from differentiating ESCs and studies of gene expression
profiles indicate that their development in culture recapitulates cardiogenesis in
the early embryo. Thus, ESCs represent a valid model to elucidate the origin
and the molecular identity of cardiovascular progenitor populations as well as
to identify key regulators of cardiac specification in mammals for which the
molecular control is largely unknown.
Cripto/ALK4/Smad2 signaling is a key pathway required for the correct
cardiac myogenesis, acting in the early phases of ESC differentiation.
Here we report the identification of the Angiotensin II Type ReceptorLike
I
(AGTRL1/
APJ/msr1) and its ligand Apelin as previously unrecognized
downstream targets of Cripto/Smad2 signaling both in vivo and in ESCs.
Gain of function experiments show that APJ suppresses neuronal
differentiation, which spontaneously occurs in cripto/
ESCs,
and restore the
cardiac program, activating the expression of genes pivotal for cardiac
specification and terminal differentiation. Furthermore, lossoffunction
experiments reveal, for the first time to our knowledge, a central role for
APJ/Apelin signaling in the gene regulatory cascade promoting ESC cardiac
specification and differentiation.
Most remarkably, we show that Apelin promotes cardiomyogenesis via
activation of pERK/p70S6 through coupling to a Go/Gi protein. Together our
data point for a previously undescribed functional link between Cripto/Smad2
and APJ/Apelin in the signaling pathways that govern mesoderm patterning
and cardiac specification in mammals.
Finally, to further investigate the role of APJ/Apelin signaling in the control of
ESC differentiation and, in particular, in the specification of cardiovascular
progenitors, we have generated an inducible ESC line, which allow
overexpression of APJ in a timespecific
manner, by using the tetracycline
(Tet)regulated
transactivator system. Our data reveal that APJ overexpression,
in an early time window of wildtype
ESC differentiation, promotes the
expression of markers of the cardiovascular lineage and markedly increases the
number of cardiomyocytes.
Downloads per month over past year
Actions (login required)
 |
Modifica documento |
