Dr. Dietrich’s lab has been working on “hunger” neurons, Agrp neurons, that are contained in the hypothalamus in animal brains. They have found that PWS-related genes, particularly Magel2, are enriched in Agrp neurons. In the second year of funding for this study, they will use a mouse model that is missing Magel2 to look at the function of the Agrp neurons from breastfeeding to adulthood, which will help identify the pathophysiology of PWS.
Dr. Theresa Strong, Director of Research Programs, shares details on this project in this short video clip.
Watch the full webinar describing all 9 research projects funded in this grant cycle here.
Prader-Willi Syndrome (PWS) is a disorder that presents both metabolic and behavior symptoms. PWS is caused by the loss of several genes in the human chromosome 15. The similarity between the PWS genes in humans and mice make the latter an attractive model to study the different aspects of this syndrome. PWS has been related to an altered function of a region in the mammalian brain, called hypothalamus. The hypothalamus is responsible for controlling essential functions, such as sleep, energy balance, and fertility. Our group has been working on a specific population of neural cells in the mammalian hypothalamus, named Agrp neurons. Agrp neurons control multiple physiological functions, including adiposity and compulsive behaviors. In preliminary studies, we found PWS related genes are enriched in Agrp neurons, mainly Magel2. Studying post-mortem brain samples from PWS subjects, others have found that gene expression in the hypothalamus is best explained by overactivation of Agrp neurons. In this project, we hypothesize Agrp neurons are overactive in PWS during development, contributing to clinical aspects of this syndrome. We will use a mouse model deficient in Magel2 to test this assumption, applying novel techniques that we have developed in our laboratory. This study will evaluate in detail the function of a neuron population from breastfeeding to adulthood in an animal model of PWS, shedding new light on the pathophysiology of PWS.
Research Outcomes: Public Summary
In this project, we focus on studying the neurodevelopment of mice that are deficient for Magel2, one of the genes involved in PWS. We developed and applied a series of state-of-the-art tools to study infant mice during the period of lactation, a period of life that offers high translatability to the human studies. First, our findings point out to an altered function of hypothalamic Agrp neurons in infant mice that are deficiency of Magel2. Agrp neurons are considered hunger-producing neurons, because when activated in adult animals they induce robust food intake. Our results show that, before these neurons control hunger for food, their function appears to be altered in Magel2 deficient mice. Further studies are needed to confirm these findings. Second, we found that Magel2 deficient mice have discrete deficits in vocal behavior when separated from their mother—i.e., infant cry response. The lower vocal behavior in the Magel2 deficient infants correlated with lower levels of maternal care towards the deficient offspring compared to wildtype offspring. Overall, our findings demonstrate phenotypic changes in a mouse model of PWS during the early postnatal period, when mice are still breastfeeding. These findings open the potential to study at the mechanistic and causal level the sources for these phenotypes at an age that has ample translational potential to the human condition.
Research Outcomes: Publications
Deficiency of the paternally inherited gene Magel2 alters the development of separation-induced vocalization and maternal behavior in mice. Bosque Ortiz, G.M., Santana, G. M., Dietrich, M.O. Genes, Brain, and Behavior. 2021; e12776.
Marcelo Dietrich, PhD
Marcelo Dietrich, PhD