2026-08-29T14:04:38Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/83422024-10-31T11:43:00Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605
Repisalud
advisor
de la Pompa, Jose Luis
author
Gomez-Apinaniz, Paula
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Fundación BBVA
funder
Fundación La Marató TV3
2019-09-12T10:03:46Z
2019-09-12T10:03:46Z
2019-06-28
10.4321/repisalud.8342
http://hdl.handle.net/20.500.12105/8342
During embryonic development, cellular interactions are crucial to orchestrate the
processes that give rise to the final body plan. The heart is the first organ to form and function
during development. The formation of trabeculae, myocardial protrusions covered by
endocardium that grow towards the lumen of the ventricles, is the first sign of chamber
development, and occurs in response to signals from the endocardium that activate the overlying
myocardium. Trabeculae are crucial for increasing the internal ventricular surface, favouring
oxygen exchange and nourishment of the cardiomyocytes.
Previous studies in mice have shown that NEUREGULIN1 (NRG1), a ligand belonging
to the Epidermal Growth Factor family expressed in the endocardium, and its more widespread
receptors -ERBB2,4- are crucial for ventricular trabeculation, but the cellular processes affected
by Nrg1 loss in the heart are not well understood. To gain an insight into the role of NRG1 in
heart development, we have used conditional loss- and gain-of-function mouse models. We have
found that endothelial-specific, Tie2Cre-mediated, Nrg1 inactivation disrupts trabecular
morphology and patterning, and reduces ventricular cardiomyocyte proliferation, while
paradoxically, the compact myocardium appeared thickened. Global gene expression analysis in
embryonic hearts by RNA-seq revealed a dysregulation of apico-basal polarity marker genes. We
thus examined whether cellular polarity and oriented cell division were affected in chamber
cardiomyocytes. We observed a loss of polarity (LAMININS-ITGα6, PKC, N-CADHERIN) in
cardiomyocytes, and an increase in parallel divisions in chamber cardiomyocytes of
Nrg1flox;Tie2Cre mutants. This finding would explain the thickened compact myocardium and the
impaired trabeculation of these mice. In addition to trabeculation defects, Nrg1flox;Tie2Cre mutant
hearts show hypoplastic valves, due to impaired epithelial-mesenchyme transition (EMT) of
presumptive valve endocardial cells, presumably because binding and activation of the receptor
ERBB2,3 by NRG1 in this region is impaired.
To study the function of NRG1 signalling at later stages of ventricular chamber
development, we have induced Nrg1 deletion during compaction, using the Cdh5CreERT2 driver.
Late Nrg1 inactivation in cardiac endothelium leads to a thinner compact myocardium, and
defective myocardial patterning and coronary vessel morphogenesis. We have also generated a
conditional gain-of-function transgenic line for NRG1. Tie2Cre-mediated Nrg1 overexpression
lead to thickened valves, and Nkx2.5Cre-mediated Nrg1 lead also to thickened valves, ventricular
septal defect and ventricular chamber dilation.
Our results indicate that NRG1 is essential from early to late stages of ventricular wall
development. NRG1 is required for cardiomyocyte polarization and oriented cell division during
trabeculation, for endocardial cushion formation during valve development, and for chamber
maturation and coronary vessel formation during compaction.
eng
Role of NRG1 in Mouse Heart Development
doctoral thesis
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TESIS PAULA GÓMEZ APIÑÁNIZ.pdf
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Table 9_RNA-seq E9.5 data.xlsx
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1. Control E10.5 heart WM IF.avi
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2. Nrg1flox;Tie2Cre E10.5 heart WM IF.avi
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3. SURVIVIN IF prophase anaphase and telophase.avi
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7. SURVIVIN IF parallel division in cytokinesis.avi
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4. SURVIVIN IF parallel division in anaphase.avi
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8. SURVIVIN IF oblique division in telophase.avi
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5. SURVIVIN IF parallel division in anaphase.avi
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6. SURVIVIN IF perpendicular division in anaphase.avi
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10. N-CADHERIN IF basal signal.avi
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11. N-CADHERIN IF lateral and basal before trabeculation.avi
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12. N-CADHERIN IF lateral signal in trabeculae.avi
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9. N-CADHERIN IF lateral signal.avi
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13. Control E16.5 heart WM IF.avi
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14. Nrg1flox,Cdh5CreE16.5 heart WM IF.avi
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16. R26Nrg1GFP,Tie2Cre E10.5 embryo GFP.avi
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17. Control E10.5 embryo.avi
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18. R26Nrg1GFP,Nkx2.5Cre E10.5 embryo GFP.avi
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15. Control E10.5 embryo.avi
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TESIS PAULA GÓMEZ APIÑÁNIZ.pdf.txt
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Table 9_RNA-seq E9.5 data.xlsx.txt