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

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

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Research Lay Summary:

Ataxia is a common neurological condition in which a person has impaired balance or coordination. Around 150,000 people in the U.S. are affected by ataxias and the worldwide occurrence rate in children is 26 out of every 100,000 individuals. One of the main etiologies for ataxia is dysfunction of the cerebellum, a major structure in the brain responsible for coordinating voluntary and involuntary motor movements. However, there is increasing evidence that the cerebellum is also important for non-motor functions such as language, social interactions, and executive function. Intriguingly, cerebellar ataxias are frequently observed in neurodevelopmental disorders with co-morbid features such as delayed development, intellectual disability, and autism, implicating the cerebellum in both motor, cognitive, and psychiatric functions. Cerebellar ataxias can result from structural insults due to stroke, cancer, or infections or genetic alterations perturbing cerebellar development and function. Sequencing technologies have improved our ability to identify the genetic causes of many cerebellar ataxias, but there remains a knowledge gap by which these gene alterations perturb cerebellar function and result in neuropsychiatric alterations. Addressing this knowledge gap through studies of single-gene disorders in animal models will improve our understanding of the molecular and cellular mechanisms underlying cerebellar ataxias.

One such single gene disorder is the condition known as the Hypotonia, Ataxia, and Delayed Development syndrome (HADDS). Individuals with this condition exhibit cerebellar ataxia, motor incoordination, global developmental delay, autistic features, and 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 and mice showed that complete loss of EBF3 homologs result in embryonic or perinatal lethality, indicating these genes are essential for the development and 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, and 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 and disrupt conserved developmental pathways like Hh and 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 and cellular mechanisms by which Ebf3 LOF perturbs the cerebellum remains to be elucidated.
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.

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