Academic journal article Genetics

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

Academic journal article Genetics

Neprilysins: An Evolutionarily Conserved Family of Metalloproteases That Play Important Roles in Reproduction in Drosophila

Article excerpt

PROTEASES play key roles in diverse physiological systems. One such family of metalloproteases, the M13 class of neutral endopeptidases, consists mainly of membranebound zinc proteases that are involved in the processing of neuropeptides and peptide hormones (reviewed in Turner et al. 2000; Turner et al. 2001; Bland et al. 2008). In mammals, seven members of this family have been identified, of which neprilysin (NEP) and endothelin converting enzyme (ECE) are the best studied. These proteins have been implicated in various diseases including cardiovascular disease (Segura and Ruilope 2011; Wick et al. 2011), Alzheimer's disease (Mulder et al. 2012; Klein et al. 2013), inflammation and inflammatory disorders (Wong et al. 2011), and cancer (Smollich et al. 2007; Maguer-Satta et al. 2011).

In addition to their role in disease, NEPs are essential for development and reproduction in mammals. The mammalian Neprilysin-2, called NL1 in mice, is highly expressed in the testis. NL1-deficient males sire fewer pups, even though spermatogenesis appears to be unaffected (Carpentier et al. 2004). In females, NEP expression in the uterus is modulated by estrogen treatment in rats (Pinto et al. 1999) and during the estrogen/progesterone cycle in humans (Head et al. 1993). In female rats and mice, controlled degradation of tachykinins, particularly substance-P, by NEP in the uterus is essential for controlling uterine contractions at different stages of pregnancy; an inability to degrade tachykinins in the uterus is associated with a reduction in litter size (Pinto et al. 1999; Pintado et al. 2003). In rats, tachykinins and their receptors have been implicated in the regulation of luteinizing hormone (LH) release (Sahu et al. 1987; Sahu and Kalra 1992; Bonavera et al. 1994). In humans, loss of function in either the tachykinin, Neurokinin B (which is preferentially deactivated by neprilysin) , or its receptor NK3-R correlates with a failure to enter puberty (Rance et al. 2010; Young et al. 2010). The exact ways in which neprilysins act to help regulate these aspects of reproduction are still largely unknown.

While the diverse role of Neps and their substrates in mammals has been the target of intense investigation, in other organisms the functions of neprilysins in reproduction are less clear. Consistent with their mammalian counterparts, neuropeptides and peptide hormones (including tachykinins) play important roles in regulating reproductive success in most organisms studied to date. In the sea squirt, Ciona intestinalis, tachykinins regulate oocyte growth (Aoyama et al. 2012). Between mammals and the zebrafish, Danio rerio, the estrogendependent features of tachykinins and their receptors appear to be conserved (Biran et al. 2012). In the insects Drosophila melanogaster and Tribolium castaneum, the tachykinin-like neuropeptide, natalisin, plays a role in regulating mating and reproductive outcomes (Jiang et al. 2013). Finally, in both the locust Locusta migratoria and the cockroach, Leucophaea maderae, the functional cleavage of tachykinins by neprilysins in the brain is conserved (Isaac and Nässel 2003).

To understand the physiological roles of neprilysins in reproduction, and by extension the neuropeptides that they regulate, we focused on this gene family in the genetically tractable model D. melanogaster. The D. melanogaster genome has 24 NEP-like genes, most of which are actively transcribed (Coates et al. 2000; Chintapalli et al. 2007; Bland et al. 2008). However, little is known about their roles in vivo. Neprilysinlike activity has been detected in extracts of larval imaginal discs and of neuronal membranes from larval and adult heads of Drosophila (Isaac et al. 2002; Wilson et al. 2002). At least two Drosophila genes, Nep2 (Bland et al. 2007) and Nep4 (Meyer et al. 2009), are active proteases with specific substrate affinities that can be inhibited with the M13-specific peptidase inhibitors thiorphan and phosphoramidon. …

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