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SPATIAL-TEMPORAL EXPRESSION OF SONIC HEDGEHOG REGULATES GROWTH, PATTERNING AND BRANCHING MORPHOGENESIS OF THE EMBRYONIC MOUSE LUNG

MILLER, LEIGH-ANNE DEBORAH
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1070490268

Abstract Details

2003, PhD, University of Cincinnati, Medicine : Molecular and Developmental Biology.
Tracheoesophageal fistula, tracheal atresia, lung hypoplasia and abrogated branching morphogenesis are pulmonary abnormalities commonly associated with loss-of-function mutations in the human and murine Sonic Hedgehog (Shh) gene. Thus Shh appears to play a role during early lung morphogenesis in branching of the lung bud and patterning of the tracheal-bronchial cartilages. Our preliminary studies detected Shh immunostaining in proximal and distal lung epithelium later in lung development suggesting that the temporal-spatial regulation of Shh may influence late lung morphogenesis. A tetracycline-inducible system was generated to express or delete Shh expression at various stages of development in order to more precisely examine the function of Shh during lung morphogenesis. Shh was expressed via doxycycline-regulated rtTA transgene directed by a lung-specific promoter from the surfactant protein C (SP-C) gene. Shh was deleted via doxycycline-regulated SP-C transgene induction of Cre recombinase expression in mice bearing floxed Shh alleles. Selective deletion of the Shh gene occurring in SP-C/rtTA-Cre-Shh flx/flx mice upon treatment with doxycycline resulted in lung-specific abnormalities that were neonatal lethal with abnormal cartilage formation in the proximal airways and altered branching morphogenesis in the peripheral lung. The effect of Shh on lung morphogenesis appears to occur from E8.5-12.5 with lesser effects on alveolarization after E15.5. Lung-specific addition of Shh substantially restored lung hypoplasia in Shh null mutant mice. From these results, Shh expression in the respiratory epithelium directs spatial patterning of the tracheal/bronchial cartilage and plays a critical role in branching morphogenesis and growth of the lung. Shh also regulates differentiation of pulmonary smooth muscle and formation of the vascular and lymphatic networks of the lung. Tracheoesophageal fistula, tracheal atresia, lung hypoplasia and abrogated branching morphogenesis are pulmonary abnormalities commonly associated with loss-of-function mutations in the human and murine Sonic Hedgehog (Shh) gene. Thus Shh appears to play a role during early lung morphogenesis in branching of the lung bud and patterning of the tracheal-bronchial cartilages. Our preliminary studies detected Shh immunostaining in proximal and distal lung epithelium later in lung development suggesting that the temporal-spatial regulation of Shh may influence late lung morphogenesis. A tetracycline-inducible system was generated to express or delete Shh expression at various stages of development in order to more precisely examine the function of Shh during lung morphogenesis. Shh was expressed via doxycycline-regulated rtTA transgene directed by a lung-specific promoter from the surfactant protein C (SP-C) gene. Shh was deleted via doxycycline-regulated SP-C transgene induction of Cre recombinase expression in mice bearing floxed Shh alleles. Selective deletion of the Shh gene occurring in SP-C/rtTA-Cre-Shh flx/flx mice upon treatment with doxycycline resulted in lung-specific abnormalities that were neonatal lethal with abnormal cartilage formation in the proximal airways and altered branching morphogenesis in the peripheral lung. The effect of Shh on lung morphogenesis appears to occur from E8.5-12.5 with lesser effects on alveolarization after E15.5. Lung-specific addition of Shh substantially restored lung hypoplasia in Shh null mutant mice. From these results, Shh expression in the respiratory epithelium directs spatial patterning of the tracheal/bronchial cartilage and plays a critical role in branching morphogenesis and growth of the lung. Shh also regulates differentiation of pulmonary smooth muscle and formation of the vascular and lymphatic networks of the lung.
Dr. Jeffrey A. Whitsett (Advisor)
209 p.
sonic hedgehog; lung morphogenesis; conditional targeting of genes

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Citations

  • MILLER, L.-A. D. (2003). SPATIAL-TEMPORAL EXPRESSION OF SONIC HEDGEHOG REGULATES GROWTH, PATTERNING AND BRANCHING MORPHOGENESIS OF THE EMBRYONIC MOUSE LUNG [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1070490268

    APA Style (7th edition)

  • MILLER, LEIGH-ANNE. SPATIAL-TEMPORAL EXPRESSION OF SONIC HEDGEHOG REGULATES GROWTH, PATTERNING AND BRANCHING MORPHOGENESIS OF THE EMBRYONIC MOUSE LUNG. 2003. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1070490268.

    MLA Style (8th edition)

  • MILLER, LEIGH-ANNE. "SPATIAL-TEMPORAL EXPRESSION OF SONIC HEDGEHOG REGULATES GROWTH, PATTERNING AND BRANCHING MORPHOGENESIS OF THE EMBRYONIC MOUSE LUNG." Doctoral dissertation, University of Cincinnati, 2003. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1070490268

    Chicago Manual of Style (17th edition)

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This open access ETD is published by University of Cincinnati and OhioLINK.