Abstract
BackgroundHighly fecund mouse strains provide an ideal model to understand the factors affecting maternal performance. The QSi5 inbred strain of mice was selected for high fecundity and low inter-litter interval, and is very successful at weaning large numbers of offspring when compared to other inbred strains.ResultsPost-natal pup weight gain was used to estimate mammary gland output and to compare the performance of QSi5 mice to CBA mice. Cumulative litter weights and individual pup weight gain was significantly higher throughout the first eight days of lactation in QSi5 mice compared to CBA mice. Morphometric analysis of mammary glands during pregnancy in QSi5 mice revealed a 150 percent greater ductal side branching compared to CBA mice (P < 0.001). Ontology and pathway classification of transcript profiles from the two strains identified an enrichment of genes involved in a number of pathways, including the MAPK, tight junction, insulin signalling and Wnt signalling. Eleven of these genes, including six genes from the MAPK signalling pathway, were identified as associated with postnatal growth. Further, positive mediators of Wnt signalling, including Wnt4, Csnk2a1 and Smad4, were over-represented in the QSi5 strain profile, while negative regulators, including Dkkl1, Ppp2r1a and Nlk, were under-represented. These findings are consistent with the role of Wnt and MAPK signalling pathway in ductal morphogenesis and lobuloalveolar development suggesting enhanced activity in QSi5 mice. A similar pattern of phenotype concordance was seen amongst 12 genes from the tight junction pathway, but a pattern did not emerge from the insulin signalling genes. Amongst a group of differentially expressed imprinted genes, two maternal imprinted genes that suppress growth induced via the IGF signalling pathway, Grb10 and Igf2r, were under-represented in QSi5 mice. Whereas Peg3 and Plagl1, both paternally imprinted genes that enhance neonatal growth, were over-represented in QSi5 mice.ConclusionWe propose that the combined action of at least three major signalling pathways involved in mammary gland development and milk secretion, namely Wnt, MAPK and tight junction pathways, contribute to the superior maternal performance phenotype in QSi5 mice. Additionally, favourable expression patterns of the imprinted genes Peg3, Plagl1, Grb10 and Igf2r may also contribute.
Highlights
Fecund mouse strains provide an ideal model to understand the factors affecting maternal performance
We identified a significant enrichment among the differentially expressed genes in the Wnt and MAPK signalling pathways, both of which are implicated as effectors of ductal side-branching during mammary gland development [2,7,8,9], and a finding that is consistent with anatomical differences found in the two strains
Significant strain-specific differences in maternal performance (P < 0.001) were observed throughout the first eight days of lactation based on the cumulative litter weight (Figure 2a)
Summary
Fecund mouse strains provide an ideal model to understand the factors affecting maternal performance. The capacity of highly fecund mouse strains to successfully reproduce is accompanied by a concomitant increase in maternal performance at sustainable litter sizes [1]. The increase in lactation demanded by larger litters can be met by a combination of physiological strategies that allow for enhanced mammary development, increased milk output and improved milk nutritional quality. The mechanisms that underpin these strategies are complex and are under the control of multiple regulatory pathways that may each contribute at various levels. An effective way to analyse these mechanisms is to identify key genes or regulatory pathways that influence lactation phenotype. Functional genomic approaches have been successfully employed to identify genes that have altered expression during mammary gland development and initiation of secretion. As a result numerous gene candidates have been implicated during different stages of the lactation cycle with some mapped to distinct signalling pathways [2,3,4]
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