CENTRAL TIME ZONE

Explore a past NAF research grant awardee’s funded study, gaining scientific insights about their Ataxia research.

Dr. Maimuna Paul will present the research, “Molecular and cellular mechanisms in EBF3-related cerebellar ataxias and neurodevelopmental disorders.”

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Research Lay Summary: The overall goal of this project is to identify the molecular and cellular mechanisms underlying EBF3-mediated regulation of cerebellum development and function using fruit fly and mouse models. My initial studies in fruit flies identified several genes that modify EBF3-mediated wing development, such as hedgehog (Hh) and MAPK/ERK signaling pathways. These evolutionarily conserved mechanisms are known to regulate both wing development in fruit flies and cerebellar development in mice. Therefore, my hypothesis is that EBF3 haploinsufficiency disrupts conserved signaling pathways during cerebellar development and result in the distinct motor and non-motor alterations observed in HADDS. Aim 1 will combine chromatin immunoprecipitation and sequencing (ChIP-seq) in the developing cerebellum of WT and Ebf3-/- (knockout, KO) mice to identify EBF3 target genes with assessments of the functional interaction between Ebf3 and MAPK/ERK and Hh-signaling pathways. Aim 2 will determine the reversibility of Ebf3 haploinsufficiency phenotypes by selectively restoring Ebf3 expression in the brain using Cre-loxP and a novel conditional Ebf3 rescue mouse allele.

The proposed study is significant because it is expected to provide key insights into the consequences of EBF3 dysfunction that are not yet explored in syndromic cerebellar ataxias. Findings from the proposed study will impact our understanding of the EBF3-dependent regulation of cerebellar development and function by identifying critical molecular pathways and determining the phenotypic reversibility of Ebf3 LOF. The innovation arises from utilizing cross-species approaches in fruit flies and mice to explore the molecular and cellular consequences of EBF3 haploinsufficiency on the development and function of cerebellar circuits, which may identify conserved pathogenic mechanisms underlying other syndromic cerebellar ataxias characterized by comorbid autism and intellectual disability.