Male mouse submaxillary gland secretes highly toxic proteins

Hiramatsu, Masahiko; Hatakeyama, Keiko; Minami, Naomi

doi:10.1007/bf01953804

Cited by 11 publications

(6 citation statements)

References 22 publications

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“…Regardless, expression of toxin homologues (and indeed toxic proteins) in oral glands is widespread in non-venomous vertebrates, for example leopard geckos (Hargreaves et al, 2014) and mice (Hiramatsu et al, 1980). Reyes-Velasco et al (2014) used this evidence from the python genome to formulate their "stepwise intermediate nearly neutral evolutionary recruitment" (SINNER) model of venom evolution, in which toxin precursor genes which are constitutively expressed at low levels in the oral glands have their expression elevated specifically in the oral gland (presumably via selection for a toxic function, though this is not specified), and then reduced in other tissues to avoid auto-toxicity (a process presumably selected for following specialisation for the toxic function).…”

Section: Genomic Data Provide Additional Insightmentioning

confidence: 99%

How the Toxin got its Toxicity

Jackson

Koludarov

2020

Front. Pharmacol.

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Venom systems are functional and ecological traits, typically used by one organism to subdue or deter another. A predominant subset of their constituent molecules—“toxins”—share this ecological function and are therefore molecules that mediate interactions between organisms. Such molecules have been referred to as “exochemicals.” There has been debate within the field of toxinology concerning the evolutionary pathways leading to the “recruitment” of a gene product for a toxic role within venom. We review these discussions and the evidence interpreted in support of alternate pathways, along with many of the most popular models describing the origin of novel molecular functions in general. We note that such functions may arise with or without gene duplication occurring and are often the consequence of a gene product encountering a novel “environment,” i.e., a range of novel partners for molecular interaction. After stressing the distinction between “activity” and “function,” we describe in detail the results of a recent study which reconstructed the evolutionary history of a multigene family that has been recruited as a toxin and argue that these results indicate that a pluralistic approach to understanding the origin of novel functions is advantageous. This leads us to recommend that an expansive approach be taken to the definition of “neofunctionalization”—simply the origins of a novel molecular function by any process—and “recruitment”—the “weaponization” of a molecule via the acquisition of a toxic function in venom, by any process. Recruitment does not occur at the molecular level or even at the level of gene expression, but only when a confluence of factors results in the ecological deployment of a physiologically active molecule as a toxin. Subsequent to recruitment, the evolutionary regime of a gene family may shift into a more dynamic form of “birth-and-death.” Thus, recruitment leads to a form of “downwards causation,” in which a change at the ecological level at which whole organisms interact leads to a change in patterns of evolution at the genomic level.

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Section: Genomic Data Provide Additional Insightmentioning

confidence: 99%

How the Toxin got its Toxicity

Jackson

Koludarov

2020

Front. Pharmacol.

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“…Kallikrein proteolytic activity releases bradykinin and promotes inflammation. Interestingly, when injected, salivary kallikreins from nonvenomous animals, such as mice and rats, induce a hypotensive crisis leading to death (63,64). In fact, Hiramatsu et al (63) effectively blurred the lines between venomous and nonvenomous mammals by proposing that male mice secrete "toxic proteins (kallikrein-like enzymes) into saliva, as an effective weapon."…”

Section: The Upr and Erad System Promoted The Evolution Of An Oral Venommentioning

confidence: 99%

“…Interestingly, when injected, salivary kallikreins from nonvenomous animals, such as mice and rats, induce a hypotensive crisis leading to death (63,64). In fact, Hiramatsu et al (63) effectively blurred the lines between venomous and nonvenomous mammals by proposing that male mice secrete "toxic proteins (kallikrein-like enzymes) into saliva, as an effective weapon." Lethality of saliva differs between mouse strains, suggesting that heritable variability in this trait exists within species, a necessary prerequisite for adaptation (65).…”

Section: The Upr and Erad System Promoted The Evolution Of An Oral Venommentioning

confidence: 99%

An ancient, conserved gene regulatory network led to the rise of oral venom systems

Barua

Mikheyev

2021

Proc. Natl. Acad. Sci. U.S.A.

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Oral venom systems evolved multiple times in numerous vertebrates enabling the exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focused strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterized the “metavenom network,” a network of ∼3,000 nonsecreted housekeeping genes that are strongly coexpressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was coopted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation, Heloderma lizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated cooption of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.

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“…For example, independent recruitment of kallikreins, most likely represents parallelism rather than constraint. Furthermore, if some animals like mice or rats indeed use salivary proteins as weapons (58), which seems plausible given that they use bites during combat for dominance, their saliva would fit common definitions of "venom" (38). If so, the evolution of envenomation in vertebrates may be much more common than currently recognized, and the line between vertebrates with and without oral venoms much less clear.…”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, when injected, salivary kallikreins from non-venomous animals, such as mice and rats induce a hypotensive crisis leading to death (58,59). In fact, Hiramatsu et al (58) effectively blurred the lines between venomous and non-venomous mammals by proposing that male mice secrete "toxic proteins (kallikrein-like enzymes) into saliva, as an effective weapon." Lethality of saliva differs between mouse strains, suggesting that heritable variability in this trait exists within species(60), a necessary prerequisite for adaptation.…”

Section: Stage 1: Exaptation Of Salivary Enzymes Particularly Kallikmentioning

confidence: 99%

An ancient, conserved gene regulatory network led to the rise of oral venom systems

Barua

Mikheyev

2020

Preprint

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Oral venom systems evolved multiple times in numerous vertebrates enabling exploitation of unique predatory niches. Yet how and when they evolved remains poorly understood. Up to now, most research on venom evolution has focussed strictly on the toxins. However, using toxins present in modern day animals to trace the origin of the venom system is difficult, since they tend to evolve rapidly, show complex patterns of expression, and were incorporated into the venom arsenal relatively recently. Here we focus on gene regulatory networks associated with the production of toxins in snakes, rather than the toxins themselves. We found that overall venom gland gene expression was surprisingly well conserved when compared to salivary glands of other amniotes. We characterised the ‘meta-venom’, a network of approximately 3000 non-secreted housekeeping genes that are strongly co-expressed with the toxins, and are primarily involved in protein folding and modification. Conserved across amniotes, this network was co-opted for venom evolution by exaptation of existing members and the recruitment of new toxin genes. For instance, starting from this common molecular foundation, Heloderma lizards, shrews, and solenodon, evolved venoms in parallel by overexpression of kallikreins, which were common in ancestral saliva and induce vasodilation when injected, causing circulatory shock. Derived venoms, such as those of snakes, incorporated novel toxins, though still rely on hypotension for prey immobilization. These similarities suggest repeated co-option of shared molecular machinery for the evolution of oral venom in mammals and reptiles, blurring the line between truly venomous animals and their ancestors.

show abstract

Male mouse submaxillary gland secretes highly toxic proteins

Cited by 11 publications

References 22 publications

How the Toxin got its Toxicity

How the Toxin got its Toxicity

An ancient, conserved gene regulatory network led to the rise of oral venom systems

An ancient, conserved gene regulatory network led to the rise of oral venom systems

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