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Doctoral Thesis
DOI
10.11606/T.42.2012.tde-16052012-100050
Document
Author
Full name
Michelle Vasconcelos
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2012
Supervisor
Committee
Santos, Marinilce Fagundes dos (President)
Lopes, Marilene Hohmuth
Ribeiro, Miriam Oliveira
Schechtman, Deborah
Sogayar, Mari Cleide
Title in Portuguese
O papel da sinalização Notch na diferenciação do epitélio pulmonar.
Keywords in Portuguese
Células ciliadas
Diferenciação celular
Epitélio
Expressão gênica
Pulmão
Sinalização Notch
Abstract in Portuguese
O epitélio pulmonar é formado por uma grande diversidade celular, que incluí: células secretoras, ciliadas, basais e neuroendócrinas (NE). A distribuição balanceada destes tipos celulares é crucial para a função pulmonar e pode ser dramaticamente alterada em doenças como a asma. Neste trabalho, estudamos o papel de Notch no pulmão em desenvolvimento ao inativar condicionalmente Rbpjk ou Pofut1, componentes críticos da sinalização Notch. Pulmões mutantes apresentaram-se superpopulados por células ciliadas e NE, além da ausência de células de Clara. Nossos dados sugeriram que Notch suprime os programas de diferenciação de células ciliadas e NE para permitir a diferenciação de células de Clara, através de um mecanismo de inibição lateral. Identificamos também genes associados com a diferenciação de células secretoras e ciliadas através de microarrays. A heterogeneidade no padrão de expressão gênica sugeriu que a via de sinalização Notch estabelece múltiplos subtipos de células ciliadas e secretoras no epitélio pulmonar em desenvolvimento.
Title in English
The role of Notch signaling in lung epithelial differentiation.
Keywords in English
Cell differentiation
Epithelium
Gene expression
Hair cells
Lung
Notch signaling
Abstract in English
The airway epithelium comprises a diverse population of secretory, ciliated, basal and neuroendocrine cells (NE). The proper balance of these cell types is critical for normal lung function and can be altered dramatically in conditions, such as asthma. We studied the role of Notch in airway progenitor cell fate by conditionally inactivating Rbpjk or Pofut1, two critical Notch pathway components in mouse mutants. This resulted in airways overpopulated with ciliated and NE cells and absence of secretory Clara cells. We found that Notch suppresses the ciliated and the NE cell programs to allow secretory cell differentiation through a lateral inhibition mechanism. We also identified genes associated with the differentiation of secretory and ciliated cells through a microarray gene profiling experiment. The great heterogeneity of gene expression patterns suggested that Notch plays a role in establishing multiple subsets of secretory and ciliated cells in the developing lung.
 
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Publishing Date
2012-06-01
 
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