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Molecular and Cellular Biology, January 2000, p. 507-515, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Role of the Distal Half of the c-Mpl Intracellular Domain in Control of Platelet Production by Thrombopoietin In Vivo

Shiuh-Ming Luoh,1 Eric Stefanich,2 Gregg Solar,3 Hope Steinmetz,3 Terry Lipari,3 Tamara I. Pestina,4 Carl W. Jackson,4 and Frederic J. de Sauvage1,*

Departments of Molecular Oncology,1 Cardiovascular,3 and Pharmacokinetics and Metabolism,2 Genentech, Inc., South San Francisco, California 94080, and Division of Experimental Hematology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105-27944

Received 17 August 1999/Returned for modification 11 October 1999/Accepted 21 October 1999

The cytokine thrombopoietin (TPO) controls the formation of megakaryocytes and platelets from hematopoietic stem cells. TPO exerts its effect through activation of the c-Mpl receptor and of multiple downstream signal transduction pathways. While the membrane-proximal half of the cytoplasmic domain appears to be required for the activation of signaling molecules that drive proliferation, the distal half and activation of the mitogen-activated protein kinase pathway have been implicated in mediating megakaryocyte maturation in vitro. To investigate the contribution of these two regions of c-Mpl and the signaling pathways they direct in mediating the function of TPO in vivo, we used a knock-in (KI) approach to delete the carboxy-terminal 60 amino acids of the c-Mpl receptor intracellular domain. Mice lacking the C-terminal 60 amino acids of c-Mpl (Delta 60 mice) have normal platelet and megakaryocyte counts compared to wild-type mice. Furthermore, platelets in the KI mice are functionally normal, indicating that activation of signaling pathways connected to the C-terminal half of the receptor is not required for megakaryocyte differentiation or platelet production. However, Delta 60 mice have an impaired response to exogenous TPO stimulation and display slower recovery from myelosuppressive treatment, suggesting that combinatorial signaling by both ends of the receptor intracellular domain is necessary for an appropriate acute response to TPO.

* Corresponding author. Mailing address: Department of Molecular Oncology, MS40, Genentech Inc., 1 DNA Way, South San Francisco, CA 94080. Phone: (415) 225-5841. Fax: (415) 225-6443. E-mail: sauvage{at}gene.com.

Molecular and Cellular Biology, January 2000, p. 507-515, Vol. 20, No. 2
0270-7306/0/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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