Abstract
This study has utilised comparative functional genomics to exploit animal models with extreme adaptation to lactation to identify candidate genes that specifically regulate protein synthesis in the cow mammary gland. Increasing milk protein production is valuable to the dairy industry. The lactation strategies of both the Cape fur seal (Artocephalus pusillus pusillus) and the tammar wallaby (Macropus eugenii) include periods of high rates of milk protein synthesis during an established lactation and therefore offer unique models to target genes that specifically regulate milk protein synthesis. Global changes in mammary gene expression in the Cape fur seal, tammar wallaby, and the cow (Bos taurus) were assessed using microarray analysis. The folate receptor α (FOLR1) showed the greatest change in gene expression in all three species [cow 12.7-fold (n = 3), fur seal 15.4-fold (n = 1), tammar 2.4-fold (n = 4)] at periods of increased milk protein production. This compliments previous reports that folate is important for milk protein synthesis and suggests FOLR1 may be a key regulatory point of folate metabolism for milk protein synthesis within mammary epithelial cells (lactocytes). These data may have important implications for the dairy industry to develop strategies to increase milk protein production in cows. This study illustrates the potential of comparative genomics to target genes of interest to the scientific community.
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References
Akers MR (2002) Lactation and the mammary gland, 1st edn. Blackwell Publishing, New York
Antony A, Tang YS, Khan RA, Biju MP, Xiao X et al (2004) Translational upregulation of folate receptors is mediated by homocysteine via RNA-heterogeneous nuclear ribonucleoprotein E1 interactions. J Clin Invest 113:285–301
Arnould JP, Boyd LL (1995) Temporal patterns of milk production in Antarctic fur seals (Arctocephalus gazella). J Zool 237:1–12
Bailey LB, Gregory JF 3rd (1999) Folate metabolism and requirements. J Nutr 129:779–782
Birn H (2006) The kidney in vitamin B12 and folate homeostasis: characterization of receptors for tubular uptake of vitamins and carrier proteins. Am J Physiol Renal Physiol 291:F22–F36
Birn H, Spiegelstein O, Christensen EI, Finnell RH (2005) Renal tubular reabsorption of folate mediated by folate binding protein 1. J Am Soc Nephrol 16:608–615
Bonner WN (1984) Lactation strategies in pinnipeds: problems for a marine mammalian group. Symp Zool Soc Lond 15:645–654
Choi SW, Mason JB (2000) Folate and carcinogenesis: an integrated scheme. J Nutr 130:129–132
Finucane KA, McFadden TB, Bond JP, Kennelly JJ, Zhao FQ (2008) Onset of lactation in the bovine mammary gland: gene expression profiling indicates a strong inhibition of gene expression in cell proliferation. Funct Integr Genomics 8:251–264
Gentleman RC, Carey VJ, Bates DM, Bolstad B, Dettling M et al (2004) Bioconductor: open software development for computational biology and bioinformatics. Genome Biol 5:R80
Georges JY, Groscolas R, Guinet C, Robin JP (2001) Milking strategy in subantarctic fur seals Arctocephalus tropicalis breeding on Amsterdam Island: evidence from changes in milk composition. Physiol Biochem Zool 74:548–559
Girard CL, Matte JJ (1998) Dietary supplements of folic acid during lactation: effects on the performance of dairy cows. J Dairy Sci 81:1412–1419
Girard C, Matte J (2005) Folic acid and vitamin B12 requirements of dairy cows: a concept to be revised. Livest Prod Sci 98:123–133
Goldsworthy SD, Crowley HM (1999) The composition of the milk of antarctic (Arctocephalus gazella) and subantarctic (A. tropicalis) fur seals at Macquaries Island. Aust Zool 47:593–603
Graulet B, Matte JJ, Desrochers A, Doepel L, Palin MF et al (2007) Effects of dietary supplements of folic acid and vitamin B12 on metabolism of dairy cows in early lactation. J Dairy Sci 90:3442–3455
Green B (1984) Composition of milk and energetics of growth. Symp Zool Soc Lond 51:369–387
Irizarry RA, Hobbs B, Collin F, Beazer-Barclay YD, Antonellis KJ et al (2003) Exploration, normalization, and summaries of high density oligonucleotide array probe level data. Biostatistics 4:249–264
Iverson SJ, Arnould JPY, Boyd IL (1997) Milk fatty acid signatures indicate both major and minor shifts in the diet of lactating Antarctic fur seals. Can J Zool 75:188–197
Jenness R (1986) Lactational performance of various mammalian species. J Dairy Sci 69:869–885
Jones ML, Nixon PF (2002) Tetrahydrofolates are greatly stabilized by binding to bovine milk folate-binding protein. J Nutr 132:2690–2694
Kamen BA, Smith AK (2004) A review of folate receptor alpha cycling and 5-methyltetrahydrofolate accumulation with an emphasis on cell models in vitro. Adv Drug Deliv Rev 56:1085–1097
Kamen BA, Johnson CA, Wang MT, Anderson RG (1989) Regulation of the cytoplasmic accumulation of 5-methyltetrahydrofolate in MA104 cells is independent of folate receptor regulation. J Clin Invest 84:1379–1386
Kane MA, Elwood PC, Portillo RM, Antony AC, Najfeld V et al (1988) Influence on immunoreactive folate-binding proteins of extracellular folate concentration in cultured human cells. J Clin Invest 81:1398–1406
Lefevre CM, Digby MR, Whitley JC, Strahm Y, Nicholas KR (2007) Lactation transcriptomics in the Australian marsupial, Macropus eugenii: transcript sequencing and quantification. BMC Genomics 8:417
Mackle TR, Dwyer DA, Ingvartsen KL, Chouinard PY, Ross DA et al (2000) Effects of insulin and postruminal supply of protein on use of amino acids by the mammary gland for milk protein synthesis. J Dairy Sci 83:93–105
Menzies KK (2008) A role for insulin to increase milk protein synthesis, Ph.D. thesis, Department of Zoology, The University of Melbourne
Menzies KK, Lefevre C, Macmillan KL, Nicholas KR (2009) Insulin regulates milk protein synthesis at multiple levels in the bovine mammary gland. Funct Integr Genomics 9:197–217
Messer M, Green B (1979) Milk carbohydrates of marsupials. II. Quantitative and qualitative changes in milk carbohydrates during lactation in the tammar wallaby (Macropus eugenii). Aust J Biol Sci 32:519–531
Naylor MJ, Oakes SR, Gardiner-Garden M, Harris J, Blazek K et al (2005) Transcriptional changes underlying the secretory activation phase of mammary gland development. Mol Endocrinol 19:1868–1883
Nicholas KR (1988) Asynchronous dual lactation in a marsupial, the tammar wallaby (Macropus eugenii). Biochem Biophys Res Commun 154:529–536
Oftedal OT, Boness DJ, Tedmam RA (1987) The behaviour, physiology, and anatomy of lactation in the Pinipedia. Curr Mammal 1:175–245
Ramanathan P, Martin I, Thomson P, Taylor R, Moran C et al (2007) Genomewide analysis of secretory activation in mouse models. J Mammary Gland Biol Neoplasia 12:305–314
Rudolph MC, McManaman JL, Hunter L, Phang T, Neville MC (2003) Functional development of the mammary gland: use of expression profiling and trajectory clustering to reveal changes in gene expression during pregnancy, lactation, and involution. J Mammary Gland Biol Neoplasia 8:287–307
Sabharanjak S, Mayor S (2004) Folate receptor endocytosis and trafficking. Adv Drug Deliv Rev 56:1099–1109
Shane B (1989) Folylpolyglutamate synthesis and role in the regulation of one-carbon metabolism. Vit Horm 45:263–335
Sharp JA, Cane K, Arnould JP, Nicholas KR (2005) The lactation cycle of the fur seal. J Dairy Res 72:81–89
Sharp JA, Cane KN, Lefevre C, Arnould JP, Nicholas KR (2006) Fur seal adaptations to lactation: insights into mammary gland function. Curr Top Dev Biol 72:275–308
Sheehy PA, Della-Vedova JJ, Nicholas KR, Wynn PC (2004) Hormone-dependent milk protein gene expression in bovine mammary explants from biopsies at different stages of pregnancy. J Dairy Res 71:135–140
Smyth GK, Speed TP (2003) Normalisation of cDNA microarray data. Methods 31:265–273
Stiening CM, Hoying JB, Abdallah MB, Hoying AM, Pandey R et al (2008) The effects of endocrine and mechanical stimulation on stage I lactogenesis in bovine mammary epithelial cells. J Dairy Sci 91:1053–1066
Trillmich F, Lechner E (1986) Milk of the Galapagos fur seal and sea lion, with a comparison of the milk of Eared seals (Otariide). J Zool 209:271–277
Urashima T, Saito T, Nakamura T, Messer M (2001) Oligosaccharides of milk and colostrum in non-human mammals. Glycoconj J 18:357–371
Warren WC, Hillier LW, Marshall Graves JA, Birney E, Ponting CP et al (2008) Genome analysis of the platypus reveals unique signatures of evolution. Nature 453:175–183
Xue GP, Snoswell AM (1985) Regulation of methyl group metabolism in lactating ewes. Biochem Int 11:381–385
Acknowledgments
This work was supported by the CRC for Co-operative Research of Innovative Dairy Products, Dairy Australia, and the Geoffrey Gardiner Foundation. The assistance of Herman Oosthuizen, John Arnould, and colleagues in the collection of Cape fur seal tissue samples is gratefully acknowledged. We also thank the captain and crew of the MV Sardinops for logistical support without which this work could not have been conducted.
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Menzies, K.K., Lefèvre, C., Sharp, J.A. et al. A novel approach identified the FOLR1 gene, a putative regulator of milk protein synthesis. Mamm Genome 20, 498–503 (2009). https://doi.org/10.1007/s00335-009-9207-4
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DOI: https://doi.org/10.1007/s00335-009-9207-4