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Molecular and Cellular Biology, January 2004, p. 407-419, Vol. 24, No. 1
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.1.407-419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Essential Role of STAT3 in Postnatal Survival and Growth Revealed by Mice Lacking STAT3 Serine 727 Phosphorylation

Yuhong Shen,1 Karni Schlessinger,2 Xuejun Zhu,1 Eric Meffre,3 Fred Quimby,4 David E. Levy,2 and J. E. Darnell Jr.1*

Laboratory of Molecular Cell Biology,1 Laboratory of Molecular Immunology,3 Laboratory Animal Research Center, The Rockefeller University, New York, New York 10021,4 Department of Pathology, New York University School of Medicine, New York, New York 100162

Received 13 May 2003/ Returned for modification 30 July 2003/ Accepted 17 September 2003

A large number of extracellular polypeptides bound to their cognate receptors activate the transcription factor STAT3 by phosphorylation of tyrosine 705. Supplemental activation occurs when serine 727 is also phosphorylated. STAT3 deletion in mice leads to embryonic lethality. We have produced mice with alanine substituted for serine 727 in STAT3 (the SA allele) to examine the function of serine 727 phosphorylation in vivo. Embryonic fibroblasts from SA/SA mice had ~50% of the transcriptional response of wild-type cells. However, SA/SA mice were viable and grossly normal. STAT3 wild-type/null (+/-) animals were also normal and were interbred with SA/SA mice to study SA/- mice. The SA/- mice progressed through gestation, showing 10 to 15% reduced birth weight, three-fourths died soon after birth, and the SA/- survivors reached only 50 to 60% of normal size at 1 week of age. The lethality and decreased growth were accompanied by altered insulin-like growth factor 1 (IGF-1) levels in serum, establishing a role for the STAT3 serine phosphorylation acting through IGF-1 in embryonic and perinatal growth. The SA/- survivors have decreased thymocyte number associated with increased apoptosis, but unexpectedly normal STAT3-dependent liver acute phase response. These animals offer the opportunity to study defined reductions in the transcriptional capacity of a widely used signaling pathway.

* Corresponding author. Mailing address: Laboratory of Molecular Cell Biology, The Rockefeller University, New York, NY 10021. Phone: (212) 327-8791. Fax: (212) 327-8801. E-mail: darnell{at}mail.rockefeller.edu.

Molecular and Cellular Biology, January 2004, p. 407-419, Vol. 24, No. 1
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.1.407-419.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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