Review
The tammar wallaby: A model system to examine domain-specific delivery of milk protein bioactives

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Abstract

The role of milk extends beyond simply providing nutrition to the suckled young. Milk has a comprehensive role in programming and regulating growth and development of the suckled young, and provides a number of potential autocrine factors so that the mammary gland functions appropriately during the lactation cycle. This central role of milk is best studied in animal models such as marsupials that have evolved a different lactation strategy to eutherians and allow researchers to more easily identify regulatory mechanisms that are not as readily apparent in eutherian species. For example, the tammar wallaby (Macropus eugenii) has evolved with a unique reproductive strategy of a short gestation, birth of an altricial young and a relatively long lactation during which the mother progressively changes the composition of the major, and many of the minor components of milk. Consequently, in contrast to eutherians, there is a far greater investment in development of the young during lactation and it is likely that many of the signals that regulate development of eutherian embryos in utero are delivered by the milk. This requires the co-ordinated development and function of the mammary gland since inappropriate timing of these signalling events may result in either limited or abnormal development of the young, and potentially a higher incidence of mature onset disease. Milk proteins play a significant role in these processes by providing timely presentation of signalling molecules and antibacterial protection for the young and the mammary gland at times when there is increased susceptibility to infection. This review describes studies exploiting the unique reproductive strategy of the tammar wallaby to investigate the role of several proteins secreted at specific times during the lactation cycle and that are correlated with potential roles in the young and mammary gland. Interestingly, alternative splicing of some milk protein genes has been utilised by the mammary gland to deliver domain-specific functions at specific times during lactation.

Highlights

► The Metatheria (Marsupialia) lineage evolved over 140 mya. ► Marsupial gestation is short and the newborn is altricial. ► Milk protein composition changes progressively during lactation. ► Milk protein bioactives target development of the mammary gland and suckled young. ► Bioactives may be domain-specific and produced by alternative splicing of genes.

Section snippets

The evolution of lactation – new models to better understand the functionality of milk

The first split in mammalian phylogeny resulted in the Prototheria approximately 200 mya and produced the monotreme lineages. Australia is the only continent on which the monotremes, platypus (Ornithorhynchus anatinus) and echidnas (Tachyglossus and Zaglosus genera) are still found. The Theria split into the Metatheria (Marsupialia) and Eutheria (Placentalia) lineages over 140 mya. The montremes can be considered the representative of the first mammals and have a sophisticated lactation

Lactation cycle of an Australian marsupial; the tammar wallaby

The advantage of studying these alternative models, apart from their intrinsic scientific interest, is that they can allow a better understanding of regulation of the lactation cycle where the kinds of controls we see are present but less obvious in other species. The lactation cycle of the marsupial has been used increasingly to better understand the role of milk for signalling development of the suckled young and the mammary gland, and mechanisms to provide protection from infection [2]. The

Milk bioactives; a role in gut development

Earlier studies have shown that pouch young fostered to mothers at a more advanced stage of lactation showed a dramatic increase in their rate of growth [20]. However, the timing of changes in the concentration of protein, lipid and carbohydrate in milk from fostered and control groups was not significantly changed by altering the sucking pattern suggesting that the developmental process in the mammary gland appears to be programmed.

These studies established a role for milk composition in

Multi-functional milk proteins; domain-specific delivery of bioactivity

Evidence is now emerging to show that milk proteins also play a significant role in the development of the mammary gland and provide antibacterial protection for the young and the mammary gland at times when there is increased susceptibility to infection. We have used the unique reproductive strategy of the tammar wallaby to investigate the role of several proteins secreted in the milk at specific times during the lactation cycle and to correlate their secretion with potential roles in the

Whey acidic protein (WAP)

Whey acidic protein (WAP) is another member of the WFDC family identified in the milk of rodents [42], [43], camels [55], pigs [56] and rabbits [57]. In addition, the protein has been found in the milk of marsupial species including tammar wallaby [58], red kangaroo [59], brush tail possum [60] and two monotremes, platypus and echidna [58], [44], [61]. Eutherian WAP genes are characterized by 4 exons and have two 4-DSC domains. In contrast, marsupial WAPs are characterized by three domains (I,

Conclusion: Regulation of mammary development and function

Given the capacity for concurrent asynchronous lactation in the tammar the regulation of mammary development and function has focused on the likelihood of a mechanism that is intrinsic to the mammary gland.

In vitro models have shown that the major milk protein genes in the tammar are regulated by insulin, cortisol and prolactin and these genes can be induced in mammary explants from late pregnant tammars [58]. However, the addition of thyroid hormone and estrogen to this hormone combination

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