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19486.pdf (1.78 MB)
ETD Abstract Container
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Pbx4 is Required to Restrict Second Heart Field and Ventricular Outflow Tract Size
Author Info
Linstrum, Kelsey
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689641
Abstract Details
Year and Degree
2015, MS, University of Cincinnati, Medicine: Molecular Genetics, Biochemistry, and Microbiology.
Abstract
Patterning of the vertebrate heart is a complex process, the failure of which can result in a variety of cardiovascular defects. Congenital cardiac outflow tract (OFT) defects account for 20-30% of all heart abnormalities. Recent work has indicated that mutations in Pbx homeodomain transcription factors are associated with OFT defects in humans, most commonly persistent truncus arteriosus (PTA). However, the mechanisms underlying these defects are not well understood. Here, we demonstrate that Pbx4 is required to limit the size of the OFT during development in zebrafish. We examined heart development in
lazarus (lzr)
zebrafish mutants, which are mutant for Pbx4, the functional equivalent of mammalian Pbx1.
Lzr
mutants have elongated hearts with variable ventricular protrusions. Interestingly, through counting cardiomyocytes, we found that
lzr
mutants have a specific increase in ventricular cardiomyocyte (VC) number.
In situ
hybridization for cardiac specification and differentiation markers indicated that the first heart field (FHF) develops correctly. However, the unique heart morphologies of
lzr
mutants begin to develop as the second heart field (SHF) extends around 24 hours post fertilization, suggesting that Pbx4 is specifically affecting SHF-derived cells. Consistent with an increase in SHF-derivatives, we find that SHF-derived smooth muscle is also significantly increased. Moreover, at these stages qPCR analysis suggests that there is an increase in the expression of SHF progenitor markers. To further test if the surplus VCs in
pbx4
deficient embryos are derived from surplus SHF progenitors, we examined VC addition through use of the photoconvertible Kaede protein and found a significant increase in VC addition compared to wild-type siblings. We show that Pbx4 functions downstream or parallel to other known effectors of OFT development retinoic acid (RA) and FGF. We also demonstrate that BMP10 may be an effector of Pbx4 as there is increased expression of BMP10 in
lzr
mutants. Altogether, our work indicates that Pbx4 is one of the first proteins found that is specifically required to limit addition of the SHF-derived VCs, which provides a novel mechanism by which OFT defects can occur in humans.
Committee
Joshua Waxman, Ph.D. (Committee Chair)
Edmund Choi, Ph.D. (Committee Member)
Jerry Lingrel, Ph.D. (Committee Member)
Pages
65 p.
Subject Headings
Genetics
Keywords
Second heart field
;
Zebrafish
;
Outflow tract
;
Pbx transcription factors
;
Heart
;
Cardiovascular defects
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Citations
Linstrum, K. (2015).
Pbx4 is Required to Restrict Second Heart Field and Ventricular Outflow Tract Size
[Master's thesis, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689641
APA Style (7th edition)
Linstrum, Kelsey.
Pbx4 is Required to Restrict Second Heart Field and Ventricular Outflow Tract Size.
2015. University of Cincinnati, Master's thesis.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689641.
MLA Style (8th edition)
Linstrum, Kelsey. "Pbx4 is Required to Restrict Second Heart Field and Ventricular Outflow Tract Size." Master's thesis, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447689641
Chicago Manual of Style (17th edition)
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Document number:
ucin1447689641
Download Count:
269
Copyright Info
© 2015, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.