Wnt signaling plays a critical role in normal development and cancer. This competitive renewal will determine the role played by the Wnt signaling in the formation of mesenchymal-derived lineages in the lung with an emphasis on parabronchial smooth muscle cells (PSMC). During organogenesis, the peristaltic movements generated by smooth muscle cells are essential to build up the internal pressure in the developing lung, physical force required for lung growth. Our proposal focuses on survival, proliferation and differentiation of the PSMC progenitors located in the peripheral mesenchyme during lung development. In the previous funding cycle, we have shown that these cells express Fgf10 and are located in the sub-mesothelial mesenchyme. These cells progressively relocate around the bronchi and under the influence of Bone morphogenetic 4, a growth factor expressed in the epithelium at high level and partially controlled by FGF10 itself, undergo differentiation into smooth muscle cells (Mailleux et al., 2005). In addition, we have also shown that FGF9, produced initially by the mesothelium was capable of maintaining the PSMC progenitors into an undifferentiated state both in vitro (del Moral et al., 2006) and in vivo (De Langhe et al., 2006). The key mechanistic paradigm that we will test in this proposal is that (-catenin signaling in the mesenchyme requires the formation of an active (-catenin/PITX2 transcriptional complex that will regulate the expression of Pitx2, Fgfr2 and c-Myc. In turn Fgfr2 and c-Myc are instrumental to control survival, proliferation and differentiation of PSMC progenitors. Central Hypothesis: (-catenin/PITX2 signaling axis in the mesenchyme controls survival, proliferation and differentiation of parabronchial smooth muscle cell progenitors during lung development in vivo.
Aim 1 : To determine the role of (-catenin signaling in the formation of the PSMCs by a loss of function approach by inactivating (-catenin throughout the lung mesenchyme (using the Dermo1Cre driver line) or in PSMC progenitors (using a Fgf10rtTA driver line). The preliminary data generated for this aim allow us to propose three sub-hypotheses that will be tested. Sub-hypothesis 1: (-catenin signaling in the mesenchyme requires the formation of a privileged (-catenin/PITX transcriptional complex. Sub-hypothesis 2: (-catenin/PITX signaling controls the expression of Fgfr2. Sub-hypothesis 3: FGFR2 signaling in the mesenchyme via PITX2 controls the formation of PSMC.

Public Health Relevance

During organogenesis, the peristaltic movements generated by smooth muscle cells are essential to build up the internal pressure in the developing lung, physical force required for lung growth. Our proposal focuses on the role of (-catenin signaling in survival, proliferation and differentiation of the parabronchial smooth muscle cells progenitors located in the peripheral mesenchyme during lung development. We propose that this work will be useful to better understand pathologies where mesenchymal cells in general (whether they are undifferentiated or not) are affected. For example, abnormal proliferation of the smooth muscle cells around the bronchi occurs in several human chronic diseases such as asthma, broncho-pulmonary dysplasia and lymphangioleiomyomatosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL074832-06S1
Application #
7824767
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
2009-06-01
Project End
2011-08-31
Budget Start
2009-06-01
Budget End
2011-08-31
Support Year
6
Fiscal Year
2009
Total Cost
$19,840
Indirect Cost
Name
Children's Hospital of Los Angeles
Department
Type
DUNS #
052277936
City
Los Angeles
State
CA
Country
United States
Zip Code
90027
Singh, Indrabahadur; Ozturk, Nihan; Cordero, Julio et al. (2015) High mobility group protein-mediated transcription requires DNA damage marker ?-H2AX. Cell Res 25:837-50
Mukhametshina, Regina T; Ruhs, Aaron; Singh, Indrabahadur et al. (2013) Quantitative proteome analysis of alveolar type-II cells reveals a connection of integrin receptor subunits beta 2/6 and WNT signaling. J Proteome Res 12:5598-608
Al Alam, Denise; Warburton, David (2013) Wingless: developmentally important genes that respond adversely to smoking. Thorax 68:703-4
Tiozzo, Caterina; Carraro, Gianni; Al Alam, Denise et al. (2012) Mesodermal Pten inactivation leads to alveolar capillary dysplasia- like phenotype. J Clin Invest 122:3862-72
Al Alam, Denise; Sala, Frederic G; Baptista, Sheryl et al. (2012) FGF9-Pitx2-FGF10 signaling controls cecal formation in mice. Dev Biol 369:340-8
Volckaert, Thomas; Dill, Erik; Campbell, Alice et al. (2011) Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury. J Clin Invest 121:4409-19
Sala, Frederic G; Del Moral, Pierre-Marie; Tiozzo, Caterina et al. (2011) FGF10 controls the patterning of the tracheal cartilage rings via Shh. Development 138:273-82
Al Alam, Denise; Green, Melissa; Tabatabai Irani, Reza et al. (2011) Contrasting expression of canonical Wnt signaling reporters TOPGAL, BATGAL and Axin2(LacZ) during murine lung development and repair. PLoS One 6:e23139
Rice, David P C; Connor, Elaine C; Veltmaat, Jacqueline M et al. (2010) Gli3Xt-J/Xt-J mice exhibit lambdoid suture craniosynostosis which results from altered osteoprogenitor proliferation and differentiation. Hum Mol Genet 19:3457-67
Parsa, Sara; Kuremoto, Koh-Ichi; Seidel, Kerstin et al. (2010) Signaling by FGFR2b controls the regenerative capacity of adult mouse incisors. Development 137:3743-52

Showing the most recent 10 out of 24 publications