Zfp423 Mechanisms in Joubert Syndrome and Related Disorders

Project Summary: This project develops cell and animal models to understand the role of a multivalent transcription factor, ZNF423, in integrating information from extracellular signaling and intracellular lineage pathways during hindbrain development. ZNF423 encodes a constitutively nuclear transcriptional regulatory protein that binds lineage differentiation factors of the EBF family and transcriptional effectors for canonical signling pathways, including SMAD, retinoic acid, and NOTCH intracellular domains. ZNF423 mutations are reported in rare Joubert syndrome (JBTS19) and nephronophthisis (NPHP14) ciliopathy patients. The ciliopathies comprise a broad family of individually rare disorders unified by signaling defects in primary cilia. Clinical presentations range mild to lethal and from primary involvement of a single organ to more pleiotropic presentations. The overwhelming majority of genes identified for ciliopathy disorders encode physical components of primary cilia. Regulatory genes that control cilium-dependent signaling and genetic modifiers that change the outcome of ciliary defects remain understudied with respect to pathogenic mechanisms and potential points for intervention in more typical cases. ZNF423 is thought to comprise an integrative node among several transcriptional complexes that respond to classical intercellular signals during brain development and to regulate SHH signaling through the primary cilium. Both reported patients and mouse models show hindbrain malformations that include hypoplasia or agenesis of the vermis. Aim 1 will test hypotheses for ZNF423 activity in canalizing information from complex signaling environments into predictable cell responses. Aim 2 will comprehensively test for modifier genes that alter cellular outcomes ex vivo in response to loss of ZNF423. Aim 3 will test hypotheses for ZNF423 participation in oligogenic brain malformations in a well-validated animal model.