Neuregulin 3 and Erbb Signalling Networks in Embryonic Mammary Gland Development Naoko Kogata & Marketa Zvelebil & Beatrice A. Howard Received: 21 January 2013 / Accepted: 26 April 2013 / Published online: 7 May 2013 # Springer Science+Business Media New York 2013 Abstract We review the role of Neuregulin 3 (Nrg3) and Erbb receptor signalling in embryonic mammary gland de- velopment. Neuregulins are growth factors that bind and activate its cognate Erbb receptor tyrosine kinases, which form a signalling network with established roles in breast development and breast cancer. Studies have shown that Nrg3 expression profoundly impacts early stages of embry- onic mammary development. Network analysis shows how Nrg/Erbb signals could integrate with other major regulators of embryonic mammary development to elicit the morpho- genetic processes and cell fate decisions that occur as the mammary lineage is established. Keywords Neuregulin 3 (Nrg3) . Erbb4 . Mammary primordium . Network Abbreviations E Embryonic day ICD Intracellular domains ME Mammary epithelium MM Mammary mesenchyme Nrg Neuregulin PI3K Phosphoinositide 3-kinase rNrg3-EGF Recombinant Neuregulin 3 epidermal growth factor domain ska Scaramanga Introduction Nrg3 is a growth factor that has been found as a regulator of the development of mammary primordium pair 3, which is the first of the five primordia pairs to form during embryonic mammogenesis in mice [1, 2]. A spontaneous hypomorphic allele of Nrg3, Nrg3 ska (scaramanga), compromises the for- mation of mammary primordium pair 3, such that it is hypo- plastic or completely absent (Fig. 1)[1, 3]. Genomic analysis of Nrg3 revealed a microsatellite repeat within intron 7 in the Nrg3 ska allele that correlates with reduced levels of Nrg3 expression [1]. Nrg3 shares high sequence identity in the extracellular EGF (epidermal growth factor)-like domain and the transmembrane domain with the Neuregulin family pro- teins [4]. Four Neuregulin genes (Nrg1-4) have been discov- ered in the mammalian genome [5, 6]. Neuregulins are cognate ligands for the Erbb transmembrane tyrosine kinase receptors and can signal in an autocrine, paracrine and juxtacrine fashion [5]. The type III isoform of Nrg1 signals in a juxtacrine, bi-directional manner, acting as a receptor for Erbb proteins and sending a back-signal into the cell express- ing type III Nrg1, but the capacity of Nrg3 to signal in this manner remains unknown [7]. A soluble extracellular frag- ment of Nrg3 is released by post-translational proteolysis which can activate Erbb4. The recombinant EGF domain of Nrg3 (rNrg3-EGF) is sufficient to induce Erbb4 receptor activation and phosphorylation [4]. Although Nrg3 binds exclusively to Erbb4, the other Erbbs that heterodimerise with Erbb4, can be activated upon binding of Nrg3 to Erbb4 [4–6]. Erbb2 is the preferred heterodimerisation partner for Erbb4 and its signal induces distinct responses compared to signalling through Erbb4 homodimers [8]. Erbb activation triggered by Neuregulins binding mediates chemotactic cell N. Kogata : M. Zvelebil : B. A. Howard (*) Division of Breast Cancer Research, Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK e-mail: beatrice.howard@icr.ac.uk J Mammary Gland Biol Neoplasia (2013) 18:149–154 DOI 10.1007/s10911-013-9286-4