Abstract/Details

Calcineurin/NFAT signaling controls B lymphocyte responses and regulates bone mass


2006 2006

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Abstract (summary)

The Ca2+-regulated calcineurin phosphatase dephosphorylates the NFATc family of transcription factors. These vertebrate specific transcription factors influence cell fate determination, morphogenesis and control cell function. We studied the role of the calcineurin/NFAT pathway in B cells by deleting the regulatory b1 subunit of calcineurin specifically in B cells. In vitro, calcineurin b1-deficient B cells have a cell-intrinsic proliferation defect downstream of the B cell receptor. In these mice, T cell independent-I antigenic responses in vivo are increased but plasma cell development and antigen specific antibody production during T cell dependent immune responses are reduced. Calcineurin is dispensable for B cell tolerance, indicating that this phosphatase complex is a critical modulator of immunogenic but not tolerogenic responses in vivo.

Development and repair of the vertebrate skeleton requires the precise coordination of osteoblasts and osteoclasts. Mice expressing a constitutively nuclear NFATc1 in osteoblasts develop high bone mass and massive osteoblast overgrowth due to increased proliferation. A coordinated change in Wnt signaling components provides a mechanism by which NFAT signaling may regulate osteoblast proliferation. Calcineurin/NFAT signaling in osteoblasts also controls the expression of monocyte chemoattractants which couple bone formation to bone resorption by attracting monocytic osteoclast precursors to bone. NFATc1 is required for osteoclasts differentiation and proper skull bone formation. Our results indicate that NFATcl is a dominant regulator of osteoblast number and orchestrates the gain and loss of bone by functioning in both osteoblasts and osteoclasts.

Patients with Down Syndrome exhibit delayed tooth eruption, defects in skeletal remodeling and alteration in craniofacial skeletal shape. Mice harboring mutations in the NFATc transcription factor genes, individually and in combination, exhibit many of the developmental defects observed in DS including the skeletal alterations. A potentially causative region of 21q, termed the Down Syndrome Critical Region, encodes DSCR-1 (a calcineurin/NFAT inhibitor) and DYRK1a (a nuclear kinase), which synergizes to inhibit NFAT activity. We propose that the 1.5-fold increase in gene dosage of DSCR1 and DYRK1a in trisomy 21 leads to reduced NFAT activity and many of the developmental manifestations of Down Syndrome.

Indexing (details)


Subject
Immunology;
Cellular biology;
Molecular biology
Classification
0982: Immunology
0758: Cellular biology
0307: Molecular biology
Identifier / keyword
Health and environmental sciences; Biological sciences; B lymphocyte; Bone mass; Calcineurin/NFAT; NFAT; Osteoporosis
Title
Calcineurin/NFAT signaling controls B lymphocyte responses and regulates bone mass
Author
Winslow, Monte Meier
Number of pages
136
Publication year
2006
Degree date
2006
School code
0212
Source
DAI-B 66/11, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542432248, 0542432242
Advisor
Crabtree, Gerald R.
University/institution
Stanford University
University location
United States -- California
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3197526
ProQuest document ID
304979776
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/304979776
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