Genomic organization of the ESP family

ESP1 turned out to be a member of a large multigene family that was unknown when we reported it in October 2005 (Kimoto et al., 2005). This novel family has been named the ESP family (Kimoto et al., 2005). In October 2005, the ESP family included 24 members, but by May 2006, the number had increased to 38 because there had been many gaps in the region of the ESP gene cluster (Fig. 6.4) (Kimoto et al., 2006). Of the 38 ESP genes, 15 are expressed in an exocrine gland around the face area, supporting the idea that the ESP gene family encodes ESP (Fig. 6.5A).

Thus, although analysis of the mouse genome is largely thought to be complete, many important genes remain to be discovered. This may be due to the fact that comprehensive proteomic studies usually target proteins larger than 10 kDa, while peptidome studies have targeted peptides smaller than 5 kDa. As a result, proteins between 5 and 10 kDa tend to be missed. Furthermore, ESP1 consists of two introns and three exons, making it difficult to predict the mature protein (Kimoto et al., 2005). Therefore, the discovery of the ESP1 has not only shed light on sexual communication via the vomeronasal system in mice but also led to a reconsideration of the comprehensiveness of so-called comprehensive bioinformatics.

The ESP gene family is clustered within a 3.2-Mb region at the telomeric end of MHC class I loci on mouse chromosome 17 (Kimoto et al., 2005) (Fig. 6.4). This is of particular interest because of two previous observations: (1) polymorphic MHC molecules have been shown to influence behavioral decisions in the context of social recognition in mice (Beauchamp and Yamazaki, 2003; Yamazaki et al., 1999) (see also the section by Yamazaki, this volume), and (2) the M10 family of MHC class I molecules is expressed in mouse vomeronasal sensory neurons (Ishii et al., 2003; Loconto et al., 2003). The genetic proximity to the MHC cluster suggests an evolutionary relationship, but the fact that the rat ESP gene family is clustered on a different chromosome than the MHC loci excludes the possibility of coevolution. In rat, there are only

ELG HG SMG

ESP1

ESP3

ESP4

ESP5

ESP6

ESP8

ESP15

ESP16

ESP18

ESP23

ESP24

ESP31

ESP34

ESP36

ELG HG SMG

ESP1 ESP36

ESP1 ESP36

ESP1 ESP36

ESP1 ESP36

Puberty

Castration Puberty

Testosterone

10 w

Puberty

10 w

ESP1 ESP36

ESP1 ESP36

10 w

Castration Puberty

10 w

ESP1 ESP36

ESP1 ESP36

Testosterone

Figure 6.5. Expression patterns of the ESP family members and sexual dimorphism in BALB/c mice.

(A) Expression patterns of the ESP family in the extraorbital lacrimal gland (ELG), the Harderian gland (HG), and the submaxillary gland (SMG). (B) Sexual dimorphic expression of ESP1 and ESP36 and testosterone dependency (see details in Kimoto et al., 2006).

ten ESPs, and homologous genes have not been found in the human genome, suggesting that the ESP gene family has undergone rapid modification during the process of evolution (Fig. 6.4) (Kimoto et al., 2006).

Sequence motifs have not been found in the ESP family, and, therefore, the origin of the ESP family remains unknown. ESP peptides range from 60 to 160 amino acids in length, and most possess a putative signal sequence motif, suggesting that they are secreted. Indeed, Western blot analysis using an anti-ESP1 antibody demonstrated that ESP1 is secreted in male tear fluid (Kimoto et al., 2005). The mature ESP1 is secreted after cleavage of the signal sequence, processing of several N-terminal amino acids, and truncation of 1-3 amino acids at the C-terminus (Kimoto et al., 2005). Thus, each ESP gene appears to encode a single polypeptide from which several isoforms are produced. Although apparent polymorphism between individuals has not been found, the possibility of differences between strains cannot be excluded. Preliminary results suggest that there are some differences in the 5'-upstream region of ESPs between BALB/c and B6 strains (Haga and Touhara, unpublished data).

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