The Use of Genetically Engineered Mice to Study PAD Biology and Pathology

Peptidylarginine deiminases (PADs or PADIs) are a family of calcium-dependent enzymes that post-translationally convert positively charged arginine residues to neutrally charged citrulline in a process called citrullination or deimination. There are five PAD family members (PAD1–PAD4 and PAD6). PAD genes arose by duplication and are clustered within a ~300-kb region on chromosome 1p36 in humans and within a ~230-kb region on chromosome 4 in mice. In both species PAD1, PAD3, PAD4, and PAD6 are grouped closely together and are oriented in the same direction, while PAD2 is set apart from the other PADs by at least 60 kb and is oriented in the opposite direction (Vossenaar et al. 2003). PAD isozymes are expressed in a range of tissues in mammals, with PAD2 being broadly expressed in numerous tissues, while PAD4 is highly represented in immune cells. PAD6 expression, on the other hand, is primarily limited to oocytes and early embryos, whereas PAD1 and PAD3 appear to be mainly expressed in the epidermis. While still coming to light, functional roles for PADs in mammalian physiology and pathology are diverse and include cellular differentiation, nerve growth, apoptosis, inflammation, gene regulation, and early embryonic development. Over the last several years, investigators have generated genetically engineered mice (GEM) for PAD2, PAD3, PAD4, and PAD6 to investigate the functions of these unique enzymes at the organismal level. Outcomes from these studies are highlighted in Fig. 4.1, and the goal of this chapter is to provide a broad summary of findings obtained from these animals.