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Dr. Maimuna Sali Paul | NAF Science Showcase

Hypotonia, Ataxia, & Delayed Development syndrome (HADDS) is one type of a single gene disorder. Individuals with this condition exhibit cerebellar ataxia, motor incoordination, global developmental delay, autistic features, & variable intellectual disabilities. Cerebellar vermian hypoplasia is the most commonly identified abnormality on brain imaging studies of individuals with HADDS. This condition is due to heterozygous loss of function (LOF) variants in Early B-cell Factor 3 (EBF3), which encodes a member of the Collier/Olf/Ebf (COE) transcription factor family. Previous studies in fruit flies & mice showed that complete loss of EBF3 homologs result in embryonic or perinatal lethality, indicating these genes are essential for the development & survival of an organism. The fruit fly homolog of EBF3, known as knot (kn), is a well-studied mediator of wing vein development, brain development, & the dendritic arborization of sensory neurons. Findings in our lab reveal that expression of pathogenic human EBF3 variants in the fruit fly is deleterious to survival & disrupt conserved developmental pathways like Hh & MAPK/ERK signaling. Preliminary studies in our lab found that loss of Ebf3 function in mice recapitulates key features of cerebellar dysfunction that are similar to features observed in individuals with HADDS. However, the molecular & cellular mechanisms by which Ebf3 LOF perturbs the cerebellum remains to be elucidated. The overall goal of this project is to identify the molecular & cellular mechanisms underlying EBF3-mediated regulation of cerebellum development & function using fruit fly & mouse models. Initial studies in fruit flies identified several genes that modify EBF3-mediated wing development, such as hedgehog (Hh) & MAPK/ERK signaling pathways. These evolutionarily conserved mechanisms are known to regulate both wing development in fruit flies & cerebellar development in mice. Therefore, my hypothesis is that EBF3 haploinsufficiency disrupts conserved signaling pathways during cerebellar development & result in the distinct motor & non-motor alterations observed in HADDS. Aim 1 will combine chromatin immunoprecipitation & sequencing (ChIP-seq) in the developing cerebellum of WT & Ebf3-/- (knockout, KO) mice to identify EBF3 target genes with assessments of the functional interaction between Ebf3 & MAPK/ERK & Hh-signaling pathways. Aim 2 will determine the reversibility of Ebf3 haploinsufficiency phenotypes by selectively restoring Ebf3 expression in the brain using Cre-loxP & 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 & function by identifying critical molecular pathways & determining the phenotypic reversibility of Ebf3 LOF. The innovation arises from utilizing cross-species approaches in fruit flies & mice to explore the molecular & cellular consequences of EBF3 haploinsufficiency on the development & function of cerebellar circuits, which may identify conserved pathogenic mechanisms underlying other syndromic cerebellar ataxias characterized by comorbid autism & intellectual disability. For more information on Ataxia, please visit our website: https://www.ataxia.org Become a Free NAF member! https://bit.ly/JoinNAF Follow us on Social Media! NAF Facebook:   / ataxiafounda.  . NAF Twitter:   / naf_ataxia   NAF Instagram:   / ataxiafound.  . Ataxia Subreddit:   / ataxia   About the Speaker: Maimuna Sali Paul, Ph.D. Bio: Dr. Paul is a postdoctoral associate in Dr. Hsiao-Tuan Chao’s lab at the Jan & Dan Duncan Neurological Research Institute, Baylor College of Medicine, Houston, Texas. She obtained her Ph.D. from Banaras Hindu University, Varanasi, India, where she studied regulation of Notch signaling in fruit flies. As a postdoctoral associate, her research focuses on disease gene discovery & elucidating the mechanisms in neurodevelopmental disorders. Dr. Paul has received NAF’s postdoctoral fellowship in 2022 for studying the EBF3-related cerebellar ataxias & neurodevelopmental disorders. Her long-term goal is to investigate the molecular mechanisms underlying cerebellar dysfunction in these disease conditions & translate the findings to therapeutics.