Genomic Analysis of Lymphoma Risk in Bullmastiff Dogs.

Lymphoma is the most common haematological malignancy affecting dogs and has a high incidence in the Bullmastiff breed. The aim of this study was to identify risk loci predisposing this breed to the disease. The average age of lymphoma diagnosis in 55 cases was less than 6 years, similar to the median age of 64 cases from our clinical and pathology databases. When fine-scale population structure was explored using NETVIEW, cases were distributed throughout an extended pedigree. When genotyped cases (n = 49) and dogs from the control group (n = 281) were compared in a genome-wide association analysis of lymphoma risk, the most prominent associated regions were detected on CFA13 and CFA33. The top SNPs in a 5.4 Mb region on CFA13 were significant at a chromosome-wide level, and the region was fine-mapped to ~1.2 Mb (CFA13: 25.2-26.4 Mb; CanFam3.1) with four potential functional candidates, including the MYC proto-oncogene bHLH transcription factor (MYC) and a region syntenic with the human and mouse lncRNA Pvt1 oncogene (PVT1). A 380 Kb associated region at CFA33: 7.7-8.1 Mb contained the coding sequence for SUMO specific peptidase7 (SENP7) and NFK inhibitor zeta (NFKBIZ) genes. These genes have annotations related to cancer, amongst others, and both have functional links to MYC regulation. Genomic signatures identified in lymphoma cases suggest that increased risk contributed by the regions identified by GWAS may complement a complex predisposing genetic background.

Cerebellar Abiotrophy in Australian Working Kelpies Is Associated with Two Major Risk Loci.

An autosomal recessive form of inherited cerebellar abiotrophy (CA) that is characterized by a degeneration of Purkinje and granule cells in the cerebellar cortex occurs in the Australian working kelpie dog breed. The clinical signs of CA include ataxia, head tremor, motor in-coordination, wide-based stance, and high-stepping gait. Investigation of clinical and pathological features indicated two closely related diseases with differences in age of onset. A genome-wide association study on 45 CA affected and 290 normal healthy Kelpies identified two significantly associated loci, one on CFA9 and a second on CFA20. Dogs homozygous for the risk haplotype on CFA20 (23 dogs) show clinical signs before ten weeks of age. Missense variants in the sixth exon of disruptor of telomeric silencing 1-like (DOT1Lp.R200Q) and in the only exon of Leucine Rich Repeat And Ig Domain Containing 3 (LINGO3p.R359C), both on CFA20, segregate with the associated risk marker which has incomplete penetrance (42%). Affected dogs homozygous for the risk haplotype on CFA9 have later onset ataxia. A missense variant in exon 5 of Vacuole Membrane Protein 1 (VMP1 p.P160Q) on CFA9 segregates as a fully penetrant Mendelian recessive with later-onset CA. Across mammals, the variety of causative loci so far identified as influencing cerebellar disorders reinforces the complexity of the pathways that contribute to cerebellar development and function, and to the pathophysiological mechanisms that may lead to cerebellar ataxia.

Altered plasma cytokines in dogs with atopic dermatitis.

BACKGROUND: Canine (Canis lupus familiaris) atopic dermatitis (AD) shares similar clinical signs to human AD. The abnormal immune response of AD is orchestrated by T lymphocytes, and may include variable involvement of cytokines, regulatory T (Treg) cells, eosinophils, mast cells and other immune components. Helper T (Th)2 cytokines often predominate initially, followed by Th1 cytokines in more chronic phases. HYPOTHESIS/OBJECTIVES: Pro-inflammatory and Treg cytokines have been shown to play a role in human AD, yet their importance is not clear in canine AD. Hence, this study aimed to measure the concentrations of cytokines/chemokines not traditionally associated with Th1/Th2 response. ANIMALS: Canine AD patients (n = 27), compared to control dogs (n = 11). METHODS AND MATERIALS: A total of 19 plasma cytokines were assayed using canine specific multiplex immuno-assays. RESULTS: The plasma concentrations of CXC Motif Chemokine Ligand 8 (CXCL8), interleukin (IL)-7 and IL-15 cytokines were elevated in canine AD patients, compared to control dogs. In addition, stem-cell factor (SCF) concentrations were reduced in the plasma of canine AD patients compared to control dogs. Distinct cytokine profiles were found in dogs belonging to the Staffordshire breeds, a group with increased risk of AD. In particular, granulocyte-macrophage colony-stimulating factor (GM-CSF) had significantly elevated concentrations. CONCLUSIONS AND CLINICAL RELEVANCE: Some of the plasma cytokine alterations in canine AD described here, particularly of IL-7, have not been reported previously. Monitoring these distinctive cytokine alterations could be useful for diagnosis and monitoring of canine AD in dogs.

Evaluating the Quality of Veterinary Students' Experiences of Learning in Clinics.

Educators seeking to evaluate the quality of students' experiences of clinic-based learning (CBL) face a challenging task. CBL programs provide multiple opportunities for learning and aim to develop a wide range of skills, knowledge, and capacities. While direct observation of learners provides important information about students' proficiency in performing various clinical tasks, more comprehensive measures are required to unpack and identify factors relating to practice readiness as a whole. This study identified variables that have a logical and statistically significant association with learning outcomes across the broad range of attributes expected of new graduate veterinarians. The research revealed that the extent of final-year veterinary students' practice readiness, as assessed by placement supervisors against criteria relevant to new graduate practice, is related to the quality of their conceptions of and approaches to CBL. Students' conceptions of and approaches to CBL were evaluated using quantitative survey instruments, with a 93% response rate (N=100) obtained for the two questionnaires. Descriptive and exploratory statistics were used to link qualitative differences in students' conceptions of and approaches to CBL with performance against criteria relevant to new graduate practice. Students who reported poorer-quality conceptions of and approaches to CBL (n=38) attained lower levels of achievement than students who reported better-quality conceptions of and approaches to CBL (n=55). Evaluation of students' conceptions of and approaches to CBL can be used by educators seeking to evaluate and improve the extent to which CBL programs are achieving their desired goals.

Therapy Development for the Lysosomal Storage Disease Fucosidosis using the Canine Animal Model.

Abstract Fucosidosis (OMIM 23000) is an inherited neurodegenerative lysosomal storage disease caused by a deficiency of the lysosomal hydrolase a-L-fucosidase due to mutations in the FUCA1 gene. Without enzyme-targeted therapy patients rarely survive beyond the first decade of life, and therapy options other than supportive care are limited. Hematopoietic transplants, first developed in the fucosidosis dog model, are the only treatment option available capable of delaying the disease course. However, due to the risks and exclusion criteria of this treatment additional therapies are required. The development of additional therapies including intravenous and intra-cerebrospinal fluid enzyme replacement therapy and gene therapy, which have been trialed in the canine model, will be discussed.

Canine atopic dermatitis: breed risk in Australia and evidence for a susceptible clade.

BACKGROUND: Genetic studies on canine atopic dermatitis (CAD) indicate that large populations from one geographical location are preferred for the identification of relevant susceptibility genes. Australian dogs are relatively isolated; studies on CAD in this population are limited. HYPOTHESIS/OBJECTIVES: To identify breeds at risk in the Australian dog population and to compare with worldwide breed predisposition. ANIMALS: Case records (n = 23,000) from University Veterinary Teaching Hospital (UVTH) dogs, including 722 with CAD. METHODS: The breed proportion of CAD and odds risk (OR) were calculated. A systematic review of 13 previous studies (1971-2010) was performed and compared to the study results by implementing an atopic dermatitis (AD)-to-reference population ratio (ADRPR). RESULTS: Eleven dog breeds with significant increased OR (≥1.0) were identified; all with breed CAD cases proportionally higher than their base hospital population. Gender risk in males from the pug dog breed (P = 0.007) was detected and the bichon frise breed had a similar trend (P = 0.05). Sixteen predisposed dog breeds were identified by systematic review. All breeds with significant increased OR in UVTH had ADRPR > 1.4; five (boxer, bulldog, Labrador retriever, pug, West Highland white terrier) were recognized as predisposed worldwide. One clade of breeds with common ancestry was highly represented in CAD cases worldwide and in Australia (81% of the significant OR cases). CONCLUSION AND CLINICAL IMPORTANCE: The use of a large population from one geographical location and ADRPR provided an objective comparison between worldwide AD studies; it identified one common clade of susceptible breeds. Breed genetics and related clinical presentation may help CAD diagnosis and treatment.

Cluster Analysis of Tumor Suppressor Genes in Canine Leukocytes Identifies Activation State.

Cells of the immune system undergo activation and subsequent proliferation in the normal course of an immune response. Infrequently, the molecular and cellular events that underlie the mechanisms of proliferation are dysregulated and may lead to oncogenesis, leading to tumor formation. The most common forms of immunological cancers are lymphomas, which in dogs account for 8%-20% of all cancers, affecting up to 1.2% of the dog population. Key genes involved in negatively regulating proliferation of lymphocytes include a group classified as tumor suppressor genes (TSGs). These genes are also known to be associated with progression of lymphoma in humans, mice, and dogs and are potential candidates for pathological grading and diagnosis. The aim of the present study was to analyze TSG profiles in stimulated leukocytes from dogs to identify genes that discriminate an activated phenotype. A total of 554 TSGs and three gene set collections were analyzed from microarray data. Cluster analysis of three subsets of genes discriminated between stimulated and unstimulated cells. These included 20 most upregulated and downregulated TSGs, TSG in hallmark gene sets significantly enriched in active cells, and a selection of candidate TSGs, p15 (CDKN2B), p18 (CDKN2C), p19 (CDKN1A), p21 (CDKN2A), p27 (CDKN1B), and p53 (TP53) in the third set. Analysis of two subsets suggested that these genes or a subset of these genes may be used as a specialized PCR set for additional analysis.

Oligodendrocyte loss during the disease course in a canine model of the lysosomal storage disease fucosidosis.

Hypomyelination is a poorly understood feature of many neurodegenerative lysosomal storage diseases, including fucosidosis in children and animals. To gain insight into hypomyelination in fucosidosis, we investigated lysosomal storage, oligodendrocyte death, and axonal and neuron loss in CNS tissues of fucosidosis-affected dogs aged 3 weeks to 42 months using immunohistochemistry, electron microscopy, and gene expression assays. Vacuole accumulation in fucosidosis oligodendrocytes commenced by 5 weeks of age; all oligodendrocytes were affected by 16 weeks. Despite progressive vacuolation, mature oligodendrocyte loss by apoptosis (caspase-6 positive) in the corpus callosum and cerebellar white matter stabilized by 16 weeks, with no further subsequent loss. Axonal neurofilament loss progressed only in late disease, suggesting that disturbed axon-oligodendrocyte interactions are unlikely to be the primary cause of hypomyelination. A 67% decline in the number of Purkinje cell layer oligodendrocytes coincided with a 67% increase in the number of caspase-6-positive Purkinje cells at 16 weeks, suggesting that early oligodendrocyte loss contributes to Purkinje cell apoptosis. Fucosidosis hypomyelination appeared to follow normal spatiotemporal patterns of myelination, with greater loss of oligodendrocytes and larger downregulation of CNP, MAL, and PLP1 genes at 16 weeks in the cerebellum versus the frontal cortex. These studies suggest that survival of oligodendrocytes in fucosidosis is limited during active myelination, although the mechanisms remain unknown.

An integrated genomics approach to identify genetic regions associated with neonatal growth trait in mice.

Neonatal growth during the early post-partum period is closely associated with lactation performance. Neonatal growth reflects milk output and is a complex variable trait among inbred mouse strains, but few studies have compared this trait systematically across more than a few strains. In the present study, 11 inbred strains of mice were measured for a neonatal growth phenotype during the first eight days of lactation. Significant differences in neonatal growth trait were observed with QSi5 (3.71±0.05 g) and DBA/1J (2.67±0.06 g) strains defining the two extremes of the phenotype. In silico association analysis was performed for trait variability using the high density SNP information on inbred strains of mice. We found strong evidence to refine a previously identified large neonatal growth QTL on mouse chromosome 9, Neogq1. When an integrated strategy that combined fine mapping and analysis of mammary transcriptome expression profiles of lactating mice with divergent phenotypes was applied, we identified neogenin (Neo1), a gene important for mammary gland morphogenesis, as a likely quantitative trait gene (QTG) underlying the Neogq1 QTL in mice.

Identification of gene sets and pathways associated with lactation performance in mice.

Mammary transcriptome analyses across the lactation cycle and transgenic animal studies have identified candidate genes for mammogenesis, lactogenesis and involution; however, there is a lack of information on pathways that contribute to lactation performance. Previously we have shown significant differences in lactation performance, mammary gland histology, and gene expression profiles during lactation [lactation day 9 (L9)] between CBA/CaH (CBA) and the superior performing QSi5 strains of mice. In the present study, we compared these strains at midpregnancy [pregnancy day 12 (P12)] and utilized these data along with data from a 14th generation of intercross (AIL) to develop an integrative analysis of lactation performance. Additional analysis by quantitative reverse transcription PCR examined the correlation between expression profiles of lactation candidate genes and lactation performance across six inbred strains of mice. The analysis demonstrated that the mammary epithelial content per unit area was similar between CBA and QSi5 mice at P12, while differential expression was detected in 354 mammary genes (false discovery rate < 0.1). Gene ontology and functional annotation analyses showed that functional annotation terms associated with cell division and proliferation were the most enriched in the differentially expressed genes between these two strains at P12. Further analysis revealed that genes associated with neuroactive ligand-receptor interaction and calcium signaling pathways were significantly upregulated and positively correlated with lactation performance, while genes associated with cell cycle and DNA replication pathways were downregulated and positively correlated with lactation performance. There was also a significant negative correlation between Grb10 expression and lactation performance. In summary, using an integrative genomic approach we have identified key genes and pathways associated with lactation performance.

Myelin genes are downregulated in canine fucosidosis.

The processes regulating the complex neurodegenerative cascade of vacuolation, neuroinflammation, neuronal loss and myelin deficits in fucosidosis, a neurological lysosomal storage disorder, remain unclear. To elucidate these processes the gene expression profile of the cerebral cortex from untreated and intrathecal enzyme replacement therapy treated fucosidosis pups and age-matched unaffected controls were examined. Neuroinflammation and cell death processes were identified to have a major role in fucosidosis pathophysiology with 37% of differentially expressed (DE) genes involved in these processes. Critical, specific, early decreases in expression levels of key genes in myelin assembly were identified by gene expression profiling, including myelin-associated glycoprotein (MAG), myelin and lymphocyte protein (MAL), and oligodendrocyte myelin paranodal and inner loop protein (OPALIN). These gene expression changes may be indicative of early neuronal loss causing reduced electrical impulses required for oligodendrocyte maturation.

Treatment of canine fucosidosis by intracisternal enzyme infusion.

The blood brain barrier is the major obstacle to treating lysosomal storage disorders of the central nervous system such as canine fucosidosis. This barrier was overcome by three, monthly injections of recombinant canine α-l-fucosidase enzyme were given intracisternally. In dogs treated from 8 weeks of age enzyme reached all areas of central nervous system as well as the cervical lymph node, bone marrow and liver. Brainstem and spinal cord samples from regions adjacent to the injection site had highest enzyme levels (39-73% of normal). Substantial enzyme activity (8.5-20% of normal controls) was found in the superficial brain compared to deeper regions (2.6-5.5% of normal). Treatment significantly reduced the fucosyl-linked oligosaccharide accumulation in most areas of CNS, liver and lymph node. In the surface and deep areas of lumbar spinal cord, oligosaccharide accumulation was corrected (79-80% reduction) to near normal levels (p<0.05). In the spinal meninges (thoracic and lumbar) enzyme activity (35-39% of normal control) and substrate reduction (58-63% affected vehicle treated samples) reached levels similar to those seen in phenotypically normal carriers (p<0.05).The procedure was safe and well-tolerated, treated (average 16%) dogs gained more weight (p<0.05) and there was no antibody formation or inflammatory reaction in plasma and CSF following treatments. The capacity of early ERT to modify progression of biochemical storage in fucosidosis is promising as this disease is currently only amenable to treatment by bone marrow transplantation which entails unacceptably high risks for many patients.

Investigation of cerebrocortical and cerebellar pathology in canine fucosidosis and comparison to aged brain.

Fucosidosis is a fatal inherited neurodegenerative disease. The pathologic changes in brain which occur with progression from preclinical to late clinical disease were investigated in fucosidosis affected dogs. As aging also causes neurodegeneration and lysosomal dysfunction, pathologic markers of fucosidosis were compared to changes in the aging canine brain. Preclinical fucosidosis cerebral cortex and cerebellum revealed early increases in all neurodegenerative markers studied including apoptosis (2.1 fold), pyramidal neuronal loss (0.9 fold decrease) and Purkinje cell loss (1.2 fold decrease) compared to age matched controls. Increased axonal spheroid formation (>100 fold in cortex, 80 fold in cerebellum), microgliosis (9.2 fold) and astrocytosis (2.1 fold in cortex and 0.5 fold in cerebellum) were distinctive features of preclinical fucosidosis brain in all regions examined. This neuropathology progressed as the dogs developed severe clinical signs, with advanced fucosidosis brain exhibiting the greatest parenchymal destruction. These measures of the neurodegenerative and inflammatory changes in fucosidosis brain will assist monitoring disease progression and response to therapy.

New graduates' conceptions of and approaches to veterinary professional practice, and relationships to achievement during an undergraduate internship programme.

New graduate veterinarians report differing experiences of the transition to practice. Some make a rapid transition to professional autonomy while others require prolonged and extensive support from their colleagues. Factors contributing to this variation are unclear. This study used phenomenography to analyse the conceptions of and approaches to veterinary professional practice (VPP) reported by new graduates in semi-structured interviews (n = 22). Quantitative statistical analysis was used to investigate links between the quality of graduates' experiences and their achievement during a comprehensive final year internship programme. Strong associations were identified between the quality of graduates' conceptions of and approaches to VPP. Links were also established between the quality of graduates' conceptions of VPP and their performance in practice prior to graduation. The outcomes of this research can be used to improve teaching and assessment during final year internships and enhance graduate attribute statements for professional degree programmes. The results also indicate that student learning research methodologies can be used to evaluate the quality of graduates' experiences in the workplace. This has implications for career outcomes research in a range of healthcare professions.

Clinical signs and neuropathologic abnormalities in working Australian Kelpies with globoid cell leukodystrophy (Krabbe disease).

OBJECTIVE: To characterize the clinical signs of globoid cell leukodystrophy (GLD) in Australian Kelpies from a working line (AWKs) and determine whether an association existed between these signs and degrees of demyelination and inflammatory responses in affected brains. DESIGN: Case-control study. ANIMALS: 4 AWKs with GLD (cases) and 7 unaffected young adult dogs of mixed breeding (controls). PROCEDURES: Clinical records were reviewed for information on signalment, and samples of neurologic tissues underwent histological processing, immunohistochemical staining, and image analysis. Findings were compared between case and control dogs. RESULTS: The 4 affected AWKs had progressive ataxia, tremors, and paresis and low leukocyte activity of galactosylceramidase, the lysosomal enzyme deficient in GLD. Image analysis of neurologic tissue revealed globoid cells characteristic of GLD and substantial demyelination in the peripheral and central nervous systems, relative to that in neurologic tissue from control dogs. This was accompanied by microglial activation, reactive astrocyto-sis, and axonal spheroid formation. CONCLUSIONS AND CLINICAL RELEVANCE: The demyelination, inflammatory responses, and axo-nal spheroids evident in the AWKs were consistent with the clinical signs of peripheral nerve, spinal cord, and cerebellar dysfunction. Because GLD is an autosomal recessive inherited disease, with considerable overlap in galactosylceramidase activity existing among heterozygotes and noncarriers, development of a molecular test is important for preventing the perpetuation of this disease in the Australian Kelpie breed.

TGF-ß1 prevents up-regulation of the P2X7 receptor by IFN-γ and LPS in leukemic THP-1 monocytes.

The P2X7 receptor is an extracellular ATP-gated cation channel critical in inflammation and immunity, and can be up-regulated by IFN-γ and LPS. This study aimed to examine the effect of TGF-ß1 on the up-regulation of P2X7 function and expression in leukemic THP-1 monocytes differentiated with IFN-γ and LPS. Cell-surface molecules including P2X7 were examined by immunofluorescence staining. Total P2X7 protein and mRNA was assessed by immunoblotting and RT-PCR respectively. P2X7 function was evaluated by ATP-induced cation dye uptake measurements. Cell-surface P2X7 was present on THP-1 cells differentiated for 3days with IFN-γ and LPS but not on undifferentiated THP-1 cells. ATP induced ethidium(+) uptake into differentiated but not undifferentiated THP-1 cells, and the P2X7 antagonist, KN-62, impaired ATP-induced ethidium(+) uptake. Co-incubation of cells with TGF-ß1 plus IFN-γ and LPS prevented the up-regulation of P2X7 expression and ATP-induced ethidium(+) uptake in a concentration-dependent fashion with a maximum effect at 5ng/ml and with an IC(50) of ~0.4ng/ml. Moreover, ATP-induced YO-PRO-1(2+) uptake and IL-1ß release were abrogated in cells co-incubated with TGF-ß1. TGF-ß1 also abrogated the amount of total P2X7 protein and mRNA induced by IFN-γ and LPS. Finally, TGF-ß1 prevented the up-regulation of cell-surface CD86, but not CD14 and MHC class II, by IFN-γ and LPS. These results indicate that TGF-ß1 prevents the up-regulation of P2X7 function and expression by IFN-γ and LPS in THP-1 monocytes. This suggests that TGF-ß1 may limit P2X7-mediated processes in inflammation and immunity.

Murine epidermal Langerhans cells and keratinocytes express functional P2X7 receptors.

Extracellular ATP via the activation of purinergic P2 receptors has an emerging role in cutaneous biology; however, the distribution of these receptors in mouse skin is poorly defined. This study investigated whether murine epidermal cell subpopulations express functional purinergic P2X(7) receptors. P2X(7) expression was examined by immunoblotting and immunofluorescence staining of epidermal cells from C57Bl/6 mice. P2X(7) function was evaluated by nucleotide-induced ethidium(+) uptake measurements in epidermal cells from C57Bl/6 mice, and from P2X(7) deficient mice and wild-type littermate controls. P2X(7) was detected in whole epidermal cell preparations, and specifically on Langerhans cells (LCs) and keratinocytes (KCs). ATP induced ethidium(+) uptake into LCs and KCs, with EC(50) values of 503 and 482 microm, respectively. BzATP, and to a lesser extent ATPgammaS and ADP, also induced ethidium(+) uptake; while UTP, alphabeta-meth-ATP and NAD were ineffective. ATP-induced ethidium(+) uptake was impaired by Na(+) and Mg(2+), and the P2X(7) antagonist, A-438079 and was absent in LCs and KCs from P2X(7) deficient mice. These results demonstrate that murine LCs and KCs express functional P2X(7), and support a role for this receptor in cutaneous biology.

The P2X(7) receptor mediates the uptake of organic cations in canine erythrocytes and mononuclear leukocytes: comparison to equivalent human cell types.

We previously demonstrated that canine erythrocytes express the P2X(7) receptor, and that the function and expression of this receptor is greatly increased compared with human erythrocytes. Using (86)Rb(+) (K(+)) and organic cation flux measurements, we further compared P2X(7) in erythrocytes and mononuclear leukocytes from these species. Concentration response curves of BzATP- and ATP-induced (86)Rb(+) efflux demonstrated that canine P2X(7) was less sensitive to inhibition by extracellular Na(+) ions compared to human P2X(7). In contrast, canine and human P2X(7) showed a similar sensitivity to the P2X(7) antagonists KN-62 and Mg(2+). KN-62 and Mg(2+) also inhibited ATP-induced choline(+) uptake into canine and human erythrocytes. BzATP and ATP but not ADP or NAD induced ethidium(+) uptake into canine monocytes, T- and B-cells. ATP-induced ethidium(+) uptake was twofold greater in canine T-cells compared to canine B-cells and monocytes. KN-62 inhibited the ATP-induced ethidium(+) uptake in each cell type. P2X(7)-mediated uptake of organic cations was 40- and fivefold greater in canine erythrocytes and lymphocytes (T- and B-cells), respectively, compared to equivalent human cell types. In contrast, P2X(7) function was threefold lower in canine monocytes compared to human monocytes. Thus, P2X(7) activation can induce the uptake of organic cations into canine erythrocytes and mononuclear leukocytes, but the relative levels of P2X(7) function differ to that of equivalent human cell types.

Transcriptome analysis identifies pathways associated with enhanced maternal performance in QSi5 mice.

BACKGROUND: Highly 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. RESULTS: Post-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. CONCLUSION: We 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.