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ucin1172693414.pdf (4.78 MB)
ETD Abstract Container
Abstract Header
Interplay of Ets Transcription Factors in the Regulation of B Cell Development
Author Info
Schweitzer, Brock L.
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1172693414
Abstract Details
Year and Degree
2007, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Abstract
Transcriptional regulation of B cell differentiation is a tightly regulated, ordered process. Expression of transcription factors during development allows for proper gene expression and cellular growth during rearrangement and expression of the immunoglobulin genes, which generate a functional B cell receptor. During hematopoietic progenitor development, expression of the Ets transcription factor PU.1 is required to drive progenitors toward an IL-7-dependent B cell fate as demonstrated by loss of B cells in PU.1-deficient mice. The primary goal of this work was to determine the function of PU.1 during B cell development. We hypothesized that PU.1 is required for immunoglobulin expression and B cell-specific gene expression. Although PU.1 is required to drive progenitors toward B cell commitment, we discovered it is dispensable for post-commitment B cell differentiation. We have demonstrated that PU.1
-/-
progenitor B(pro‑B) cells are capable of rearrangement and expression of the IgH locus and expression of certain pre-B cell markers, but are deficient in Igλ and FcγRIIb expression. This suggests that PU.1 is not required for pro‑B cell gene expression, but is required for other B cell specific genes. This poses a paradox that, in order to promote B cell differentiation and expression of B cell-specific genes, PU.1 must be inhibited and also active. We hypothesized that another Ets family member, Spi‑C, modulates PU.1 activity during B cell development. When Spi‑C is ectopically expressed in pro‑B cells, these cells display a similar phenotype to PU.1
-/-
pro‑B cells, suggesting that Spi‑C can interfere with PU.1 activity. Since Spi‑C is expressed at discrete stages during B cell development, we propose that Spi‑C solves this paradox of PU.1 expression by interfering with PU.1 activity temporally when PU.1 inhibits gene expression and subsequent differentiation. Reduction of Spi‑C expression in other stages permits PU.1 B cell-specific gene expression when required. We also observe a potential role for Spi‑C in driving B‑1 cell development, since the B‑2 cell marker, B220, is reduced in both PU.1
-/-
and Spi‑C ectopically expressing pro‑B cells. This work has pioneered in vivo study of PU.1 in B cell development and also laid the foundations for the function of Spi‑C.
Committee
Dr. Rodney DeKoter (Advisor)
Pages
154 p.
Keywords
transcription factors
;
B cell
;
immunoglobulins
;
PU.1
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Refworks
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RIS
Mendeley
Citations
Schweitzer, B. L. (2007).
Interplay of Ets Transcription Factors in the Regulation of B Cell Development
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1172693414
APA Style (7th edition)
Schweitzer, Brock.
Interplay of Ets Transcription Factors in the Regulation of B Cell Development.
2007. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1172693414.
MLA Style (8th edition)
Schweitzer, Brock. "Interplay of Ets Transcription Factors in the Regulation of B Cell Development." Doctoral dissertation, University of Cincinnati, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1172693414
Chicago Manual of Style (17th edition)
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Document number:
ucin1172693414
Download Count:
691
Copyright Info
© 2007, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.