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Left-right patterning disturbance can cause severe birth defects, but it remains least understood of the three body axes. We uncovered an unexpected role for metabolic regulation in left-right patterning. Analysis of the first spatial transcriptome profile of left-right patterning revealed global activation of glycolysis, accompanied by right-sided expression ofBmp7and genes regulating insulin growth factor signaling. Cardiomyocyte differentiation was left-biased, which may underlie the specification of heart looping orientation. This is consistent with knownBmp7stimulation of glycolysis and glycolysis suppression of cardiomyocyte differentiation. Liver/lung laterality may be specified via similar metabolic regulation of endoderm differentiation.Myo1d, found to be left-sided, was shown to regulate gut looping in mice, zebrafish, and human. Together these findings indicate metabolic regulation of left-right patterning. This could underlie high incidence of heterotaxy-related birth defects in maternal diabetes, and the association of PFKP, allosteric enzyme regulating glycolysis, with heterotaxy. This transcriptome dataset will be invaluable for interrogating birth defects involving laterality disturbance.

MYC proto-oncogene dysregulation alters metabolic, translational, cell cycle and other functions in ways that support tumor induction and maintenance. Myc+/- mice are healthier and longer-lived than control mice but the long-term ramifications of more complete Myc loss remain unknown. We now describe the life-long consequences of body-wide Myc inactivation initiated post-natally. “MycKO” mice rapidly acquire numerous features of premature aging including altered body composition and habitus, metabolic dysfunction, hepatic steatosis and the dysregulation of numerous gene sets involved in functions that normally deteriorate with aging. Yet, MycKO mice have an extended life span that correlates with a 4-5-fold lower lifetime cancer incidence. Aging tissues from normal mice and humans deregulate many of the same gene sets as do young MycKO mice while also down-regulating Myc and many of its target genes. Normal aging and its associated cancer predisposition are thus highly linked via Myc and its target genes and can be genetically separated.

Neuroblastoma, the most common extracranial solid malignancy in children, accounts for 15% of pediatric cancer deaths despite multimodal therapy including surgical resection. Unfortunately, complete surgical resection remains challenging due to encasement of major neurovascular structures, unclear tumor margins, and remote nodal disease. While mouse models of neuroblastoma are extremely valuable for studying tumor biology and medical treatments, the small size renders the mouse model insufficient to evaluate novel surgical therapy.Here, we have developed a novel rat model of neuroblastoma to facilitate further development of surgical treatment. Human neuroblastoma cells (SK-N-BE(2)) were injected into the adrenal gland of RNU nude rats. They developed 2 cm xenograft tumors at 5 weeks which were easily identifiable on MRI imaging and on visual inspection. The rats began losing weight and neared end stage at 7 weeks, at which point surgical resection was attempted. While surgical resection was technically feasible, the rats were too frail to survive surgery at the late stage. The pathology of the tumors was consistent with neuroblastoma: small round blue cells with strong PHOX2B staining. Thus, we present a novel rat neuroblastoma model that can be used for development of surgical techniques, such as the use of intraoperative contrast agents.

Polyamines (putrescine, spermidine, and spermine) are essential molecules for normal cellular functions and are subject to strict metabolic regulation. Mutations in the gene encoding spermine synthase (SMS) lead to accumulation of spermidine in an X-linked recessive disorder known as Snyder-Robinson syndrome (SRS). Presently, no treatments exist for this rare disease that manifests with a spectrum of symptoms including intellectual disability, developmental delay, thin habitus, and low muscle tone. The development of therapeutic interventions for SRS will require a suitable disease-specific animal model that recapitulates many of the abnormalities observed in patients.Here, we characterize the molecular, behavioral, and neuroanatomical features of a mouse model with a missense mutation inSmsgene that results in a glycine-to-serine substitution at position 56 (G56S) of the SMS protein. Mice harboring this mutation exhibit a complete loss of SMS protein and elevated spermidine/spermine ratio in skeletal muscles and the brain. In addition, the G56S mice demonstrate increased anxiety, impaired learning, and decreased explorative behavior in fear conditioning, Morris water maze, and open field tests, respectively. Furthermore, these mice failed to gain weight over time and exhibit abnormalities in brain structure and bone density. Transcriptomic analysis of the cerebral cortex revealed downregulation of genes associated with mitochondrial oxidative phosphorylation and ribosomal protein synthesis. Our findings also revealed impaired mitochondrial bioenergetics in fibroblasts isolated from the G56S mice, indicating a correlation between these processes in the affected mice. Collectively, our findings establish the first in-depth characterization of an SRS preclinical mouse model that identifies cellular processes that could be targeted for future therapeutic development.

GM3 synthase (GM3S) deficiency is a rare neurodevelopmental disorder caused by an inability to synthesize gangliosides, for which there is currently no treatment. Gangliosides are brain-enriched, plasma membrane glycosphingolipids with poorly understood biological functions related to cell adhesion, growth, and receptor-mediated signal transduction. Here, we investigated the effects of GM3S deficiency on metabolism and mitochondrial function in a mouse model. By indirect calorimetry, GM3S knockout mice exhibited increased whole-body respiration and an increased reliance upon carbohydrate as an energy source.