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Molecular and Cellular Biology, August 2006, p. 5809-5826, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00024-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Acute Myeloid Leukemia-Associated Mkl1 (Mrtf-a) Is a Key Regulator of Mammary Gland Function{dagger}

Yi Sun,1 Kelli Boyd,2 Wu Xu,3 Jing Ma,4 Carl W. Jackson,5 Amina Fu,1 Jonathan M. Shillingford,6,{ddagger} Gertraud W. Robinson,6 Lothar Hennighausen,6 Johann K. Hitzler,7 Zhigui Ma,1 and Stephan W. Morris1,5*

Department of Pathology,1 Animal Resource Center,2 Department of Biochemistry,3 Hartwell Center for Bioinformatics and Biotechnology,4 Department of Hematology-Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,5 Laboratory of Genetics and Physiology, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892,6 Department of Paediatrics, Division of Haematology/Oncology, Program in Developmental Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada7

Received 5 January 2006/ Returned for modification 21 February 2006/ Accepted 17 May 2006

Transcription of immediate-early genes—as well as multiple genes affecting muscle function, cytoskeletal integrity, apoptosis control, and wound healing/angiogenesis—is regulated by serum response factor (Srf). Extracellular signals regulate Srf in part via a pathway involving megakaryoblastic leukemia 1 (Mkl1, also known as myocardin-related transcription factor A [Mrtf-a]), which coactivates Srf-responsive genes downstream of Rho GTPases. Here we investigate Mkl1 function using gene targeting and show the protein to be essential for the physiologic preparation of the mammary gland during pregnancy and the maintenance of lactation. Lack of Mkl1 causes premature involution and impairs expression of Srf-dependent genes in the mammary myoepithelial cells, which control milk ejection following oxytocin-induced contraction. Despite the importance of Srf in multiple transcriptional pathways and widespread Mkl1 expression, the spectrum of abnormalities associated with Mkl1 absence appears surprisingly restricted.

* Corresponding author. Mailing address: Departments of Pathology and Hematology-Oncology, Thomas Tower, Room 4026, Mail Stop 343, 332 North Lauderdale St., Memphis, TN 38105. Phone: (901) 495-3616. Fax: (901) 495-2032. E-mail: steve.morris{at}stjude.org.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} Present address: Life Sciences and Technology Building, Lab 2203, Molecular, Cellular and Developmental Biology, University of California, Santa Barbara, CA 93106-9610.

Molecular and Cellular Biology, August 2006, p. 5809-5826, Vol. 26, No. 15
0270-7306/06/$08.00+0     doi:10.1128/MCB.00024-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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