Steunfonds Marguerite-Marie Delacroix: A multi-omics approach to address neuronal development upon ZFHX4 deficiency

01 January 2023 → 31 December 2024
Funding by bilateral agreement (private and foundations)
Research disciplines
  • Medical and health sciences
    • Genetics
    • Developmental neuroscience
ZFHX4 neurodevelopmental disorders zebrafish CRISPR
Project description

Neurodevelopmental disorders (NDDs) result from impaired development and functioning of the brain. We have recently identified loss-of-function variation in ZFHX3 as a novel cause for syndromic intellectual disability (ID). In this follow-up study, we plan to study the role of ZFHX4 - a transcription factor from the Zinc Finger homeobox gene family, sharing 52% homology with ZFHX3 – in neurodevelopment. In collaboration with Dr. Palomares (Madrid, Spain), we gathered an international cohort of 47 individuals with ID, short stature and recurrent facial dysmorphisms, all harboring loss-of-function aberrations affecting ZFHX4. To better understand how loss of function of ZFHX4 can lead to disease, we will determine the binding partners as well as (in)direct target genes of ZFHX4 during normal neuronal differentiation.

Moreover, by performing CRISPR-Cas9 genome engineering and ectopically induce ZFHX4 in neural stem cells; the molecular, morphological, and electrophysiological effects of aberrant ZFHX4 expression will be studied in relevant in vitro model systems.

As in vitro systems do not fully recapitulate the phenotype associated with ZFHX4 deficiency, we will also generate an in vivo zebrafish knockout model to study the phenotypical effects of ZFHX4 aberrations.

To conclude, the main objective is to further determine the function of ZFHX4 in neural development and assess how its dysfunction can be linked to ID.