A mouse model of HUWE1 syndrome - Abstract Protein ubiquitination is crucial for cellular homeostasis, impacting protein quality control and the regulation of signaling molecules. HUWE1, a ubiquitin E3 ligase, ubiquitinates a variety of substrates, including p53 and MYC, and its role in development and disease is not fully understood. Mutations in HUWE1 have been linked to rare mental disorders and intellectual disabilities. Notably, many of these mutations occur in the catalytic HECT domain, suggesting altered HUWE1 activity. However, the relationship between these mutations and neurological conditions remains unclear, partly due to the absence of an appropriate animal model. To address this, we generated a Huwe1R4190C knock-in mouse model carrying a mutation corresponding to a frequently reported mutation in human HUWE1. Preliminary observations indicate that these mice exhibit decreased social exploration and object recognition. Our overarching objective is to characterize the neural development of these mice to understand how HUWE1 mutations contribute to mental and intellectual disorders. Our central hypothesis posits that the Huwe1R4190C mutation disrupts normal HUWE1 function, leading to abnormal protein degradation and subsequent dysregulation of neuronal proliferation, differentiation, and synaptic function. We will test this through two specific aims: (1) to determine the impact of the Huwe1R4190C mutation on neural progenitor proliferation and neuronal differentiation in the developing brain, and (2) to investigate whether the Huwe1R4190C mutation affects excitatory and inhibitory synapse formation in the postnatal brain. This pilot study will elucidate the role of the Huwe1R4190C mutation in neural development and provide a valuable model for future HUWE1 research, laying the groundwork for subsequent studies on the molecular mechanisms underlying HUWE1-related neurodevelopmental disorders. Additionally, the insights gained from this study could inform potential therapeutic strategies targeting HUWE1-associated pathologies. The successful completion of these aims will also position us to pursue a competitive multi-PI R01 application, fostering collaborative research efforts within the Brain Health Research Institute (BHRI) at Kent State University. By establishing a comprehensive understanding of HUWE1’s role in brain development, we aim to make significant contributions to the field of neurogenetics.
