Enabling temporal and spatial restriction of MYT1L to identify molecular and postnatal circuit-level druggable targets

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Project Summary Putative loss of function mutations in the MTY1L gene lead to a newly defined intellectual and developmental syndrome, yet the neurobiological mechanisms underlying this relationship remain unknown. MYT1L Syndrome is characterized by global developmental delay (particularly in motor and language development), intellectual disability, highly penetrant obesity and hypotonia, and a significant subset with autism spectrum disorder and/or attention-deficit/hyperactivity disorder. Other symptoms of variable penetrance include epilepsy, microcephaly, white-matter thinning, and neuroendocrine disruptions. Thus far, about 100 patients have been described clinically and prevalence estimates are ~1:2000. However, the function of MYT1L has just begun to be studied, therefore, we currently know very little about how MYT1L loss of function mutations result in disease. We recently developed the first MYT1L haploinsufficient mouse model, which successfully recapitulated many of the patient phenotypes, including hyperactivity, changes in communicative behavior, social behavior challenges, muscle hypotonia, microcephaly, and obesity. We also identified disrupted gene expression, precocious neuronal differentiation as a mechanism for microcephaly, and failure of transcriptional and chromatin maturation in adults. Thus, with this model, we enhanced the understanding of MYT1L function and established a preclinical model of MYT1L Syndrome. However, it is unknown when during development, and where in the brain the disruption of MYT1L protein leads to each specific clinically-relevant phenotype. This is because we lack the ability to clearly define the relevant molecular and circuit-level targets of MYT1L, identification of which would enable studies of potential rescue therapies. To begin to address these holes, we recently generated a MYT1L conditional model targeting the same exon as our constitutive haploinsufficient model to allow for spatial and temporal restriction of MYT1L loss. The goal of this project is to validate this tool for temporal and spatial applications, and to determine the extent to which postnatal MYT1L function is responsible for the phenotypes observed in adults and identify the genes regulated by MYT1L in the postnatal brain. Such insights will serve to help define druggable molecular and circuit targets, as well as therapeutic temporal windows for MYT1L syndrome. In Aim 1, we will validate our new tool for inducing MYT1L loss in a temporally and spatially controlled manner and for enabling studies of molecular targets for potential therapeutic action. A fundamental question we must answer to develop therapeutic strategies for this rare disease is if MYT1L loss disrupts neurodevelopment (i.e, in the embryo) or neuromaintenance (i.e., postnatally, and in adults). In order to address this question, in Aim 2, we will leverage our new conditional model and inducible Cre-recombinase genetic tools to induce loss of MYT1L in the postnatal brain, after completion of early neurodevelopment, and determine which phenotypes are due to the postnatal functions of MYT1L. Ultimately, this tool will guide future studies into targeted therapies for MYT1L Syndrome, and potentially other related IDDs.