Cttn is ubiquitously expressed, however, in haematopoietic cells its homologue HS1 is the major form. It is a target for both kinases and acetylases, post-translational modifications which regulate its F-actin binding activity and subsequent role in dynamic actin processes. In addition, it can act as a scaffolding protein due to its ability to interact with a wide range of molecules (Reviewed in ). Ĭttn is an F-actin binding protein which can interact with the actin nucleation promoting factor, the Arp2/3 complex and stabilise dynamic branched actin networks. Furthermore, the Arp2/3 complex is regulated by a number of different proteins including the cortactin (Cttn) family of proteins (Cttn & haematopoietic lineage cell-specific protein 1 (HS1)). Both of these structures are dependent on WASp-Arp2/3-mediated actin polymerisation for proper formation. Recent studies have shown that podosomes, and the subsequent degradation of extracellular matrix, are required for proplatelet protrusion through the basement membrane of the blood vessel during the later stages of platelet formation, and that actin nodules are platelet podosome-like structures which contribute to platelet aggregate stability under flow. Two actin-related structures which have been identified in platelets and megakaryocytes are the actin nodule and the podosome, respectively. Similarly, many cytoskeletal proteins have been shown to be required for proper platelet function including Filamin A, WASp, myosin, and α-actinin. Several proteins, which are either part of the cytoskeleton or regulate its organisation (including mDia1, WASp, Myosin, profilin and ADF/Cofilin), have been shown to be important for producing sufficient platelets of the correct size. The actin cytoskeleton plays a critical role in both the production of platelets from megakaryocytes and in the proper functioning of platelets. We conclude that despite the importance of WASp and the Arp2/3 complex in regulating F-actin dynamics in many cells types, the role of cortactin in their regulation appears to be fulfilled by other proteins in platelets. In addition, platelet actin nodules, and megakaryocyte podosomes, actin-based structures known to be dependent on WASp and the Arp2/3 complex, formed normally. No effect on tail bleeding time or in thrombosis models was observed.

Platelet function was also unaffected by loss of Cttn/HS1 with no differences observed in a range of platelet function assays including aggregation, secretion, spreading, clot retraction or tyrosine phosphorylation.

These mice had normal platelet production, with platelet number, size and surface receptor profile comparable to controls. We generated mice lacking Cttn and HS1 in the megakaryocyte/platelet lineage.

The cortactin family of proteins (Cttn & HS1) are known to regulate WASp-Arp2/3-mediated actin polymerisation in other cell types and so here we address the role of these proteins in platelets using knockout mouse models. In platelets and megakaryocytes, these proteins have been shown to be important for proper platelet production and function. The Wiskott Aldrich Syndrome protein (WASp) and Actin-Related Proteins 2 & 3 Complex (Arp2/3 complex) are critical mediators of actin polymerisation and organisation in many cell types. A dynamic, properly organised actin cytoskeleton is critical for the production and haemostatic function of platelets.

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