There are few documented instances in which human organs are able to respond to injury by complete and perfect replacement of the damaged parts. Under the appropriate conditions the adult digit is one such organ. The digit is composed of a diverse number of distinct cell types making up the various tissues of the digit (e.g. epidermis, nail, nailbed, dermis, adipose, bone, etc.), and in response to amputation, a perfect replica of the tip of the digit including the nail and fingerprint regenerates. Surprisingly little is in fact known about the digit regeneration process in humans, or other mammals, yet the potential for clinical impact seems reasonably high. Using a mouse model we provide evidence that BMP signaling and Msxl function is required for a successful regeneration response in the mouse fetal digit. In this application we propose studies to elucidate the mechanisms by which BMP signaling and Msxl activity regulates fetal digit regeneration.
4 specific aims are proposed. In the first aim we will explore the role of BMP signaling in the in vivo control of fetal digit regeneration by testing the hypothesis that endogenous BMP4 signaling is a regulator of regeneration. In the second aim we will utilize mutations of two type I BMP receptors (Bmpr-IA and Bmpr-IB) in combination with lentivirus mediated expression of constitutively active and dominant negative receptor forms to investigate the mechanism of BMP signaling in digit regeneration. In the third aim we will test the hypothesis that the transcriptional regulator Runx2/Cbfal functions downstream of Msxl and BMP4 in the regeneration response. In the fourth aim we focus on the role that Msxl plays in the formation of a regeneration competent wound epidermis. The long-term goal of this project is to understand the molecular requirements for digit regeneration with the intent of enhancing regenerative capabilities. The results from these studies will impact both clinical and basic sciences. ? ? ?

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD043277-05
Application #
7389729
Study Section
Development - 1 Study Section (DEV)
Program Officer
Javois, Lorette Claire
Project Start
2004-02-17
Project End
2010-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
5
Fiscal Year
2008
Total Cost
$310,475
Indirect Cost
Name
Tulane University
Department
Anatomy/Cell Biology
Type
Schools of Arts and Sciences
DUNS #
053785812
City
New Orleans
State
LA
Country
United States
Zip Code
70118
Lee, Jangwoo; Marrero, Luis; Yu, Ling et al. (2013) SDF-1?/CXCR4 signaling mediates digit tip regeneration promoted by BMP-2. Dev Biol 382:98-109
Wu, Yuanyuan; Wang, Karen; Karapetyan, Adrine et al. (2013) Connective tissue fibroblast properties are position-dependent during mouse digit tip regeneration. PLoS One 8:e54764
Yu, Ling; Han, Manjong; Yan, Mingquan et al. (2012) BMP2 induces segment-specific skeletal regeneration from digit and limb amputations by establishing a new endochondral ossification center. Dev Biol 372:263-73
Fernando, Warnakulasuriya Akash; Leininger, Eric; Simkin, Jennifer et al. (2011) Wound healing and blastema formation in regenerating digit tips of adult mice. Dev Biol 350:301-10
Yu, Ling; Han, Manjong; Yan, Mingquan et al. (2010) BMP signaling induces digit regeneration in neonatal mice. Development 137:551-9
Song, Yiqiang; Yan, Mingquan; Muneoka, Ken et al. (2008) Mouse embryonic diastema region is an ideal site for the development of ectopically transplanted tooth germ. Dev Dyn 237:411-6
Muneoka, Ken; Allan, Christopher H; Yang, Xiaodong et al. (2008) Mammalian regeneration and regenerative medicine. Birth Defects Res C Embryo Today 84:265-80
Han, Manjong; Yang, Xiaodong; Lee, Jangwoo et al. (2008) Development and regeneration of the neonatal digit tip in mice. Dev Biol 315:125-35
Yu, Ling; Liu, Hongbing; Yan, Mingquan et al. (2007) Shox2 is required for chondrocyte proliferation and maturation in proximal limb skeleton. Dev Biol 306:549-59
Han, Manjong; Yang, Xiaodong; Taylor, Gail et al. (2005) Limb regeneration in higher vertebrates: developing a roadmap. Anat Rec B New Anat 287:14-24