Will Renthal, from the Greenberg lab, described recently discovered sites on MeCP2 that are modified in response to neuronal activity. Because neuronal activity is critical for normal neurodevelopment and function, Will is investigating how these activity-dependent modifications of MeCP2 are relevant to the pathophysiology of Rett. He is also following up on the lab’s recent discovery that MeCP2 deficiency leads to the misregulation of numerous very long genes. He is using pharmacologic and genetic approaches to reverse this long gene misregulation in mouse models of Rett syndrome.
"It was a fantastic meeting. I can’t tell you how privileged I feel to get to work with this Consortium. Hearing the stories from the parents (RSRT trustees) who attended and seeing how hard RSRT works simultaneously provides important perspective to our research but also acts as a jolt of energy to get back in the lab to solve this problem!" - Will Renthal
A massive effort from Consortium scientists as well as many other researchers is to identify the genes that MeCP2 regulates and to understand how this regulation occurs. Benyam Kinde, an MD/PhD student in the Greenberg lab has been studying how DNA, and modifications of DNA (such as DNA methylation), dictate where and how MeCP2 regulates the expression of genes that are critical to brain function.
Sabine Lagger of the Bird lab is studying the genomic sites where MeCP2 protein binds. She is re-evaluating published gene expression data sets and finds that loss of MeCP2 affects a defined small set of neuronal genes yet also observes a total dampening of general protein production. She is now focused on determining whether the up-regulation of neuronal genes or the down-regulation of a vast majority of transcribed genes is the cause of Rett Syndrome.
"The meeting was extremely interesting as I heard about new techniques and research directions to tackle some of the most pressing questions in the Rett Syndrome field. Also, the input of consortium members regarding my talk was very helpful." - Sabine Lagger
Aurel Nagy, also of the Greenberg lab, presented his efforts to investigate individual cells one at a time. The brain is an incredibly complex organ made up of diverse cells that differ from one another in shape, size, and electrical behavior. Current sequencing techniques require looking at many cells at once to detect any signal, and unfortunately doing so means losing sight of the subtle contributions these differences may have. It's sort of like studying a smoothie to try and understand the properties of a fruit salad: we can get quite far, but will never quite have the full picture. Aurel discussed a single cell sequencing technology called inDrops that was published by his collaborator Allon Klein. He explained how the inDrops technique works, presented some preliminary data and discussed the many ways the lab will be applying inDrops to better understand Rett syndrome in the near future.
Susan Su in the Greenberg lab is generating a mouse 'connectome' of Rett Syndrome in order to examine how the cellular morphology and synaptic connections are altered at the ultrastructural level. This is an enormous project that requires painstaking attention.
"The Consortium meetings are great opportunities to share preliminary data and receive feedback for our experiments. It is exciting to be a part of a larger group in which we all share a common goal of gaining a deeper understanding of MeCP2."- Susan Su
Benjamin Rakela of the Mandel lab brought a different perspective to the meeting by discussing his studies on astrocytes (abundant star-like glial cells). Ben explores how astrocytes modulate neuronal signaling and how this interaction is affected in Rett syndrome. He has found that astrocyte-mediated processes are deficient in Rett syndrome, but that they can be rescued with the re-expression of MeCP2.
Ben’s colleague, John Sinnamon, discussed his ongoing effort to treat Rett by harnessing the catalytic activity of an enzyme already found in cells to target and correct mutations in MeCP2 RNA. This is an exciting approach with clear clinical ramifications.