ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling

ZC4H2 encodes a C4H2 type zinc-finger nuclear factor,the mutation of which has been associated with disorders with various clinical phenotypes in human,including developmental delay,intellectual disability and dystonia.ZC4H2 has been suggested to regulate spinal cord patterning in zebrafish as a co-factor for RNF220,an ubiquitin E3 ligase involved in Gli signaling.Here we showed that ZC4H2 and RNF220 knockout animals phenocopy each other in spinal patterning in both mouse and zebrafish,with mispatterned progenitor and neuronal domains in the ventral spinal cord.We showed evidence that ZC4H2 is required for the stability of RNF220 and also proper Gli ubiquitination and signaling in vivo.Our data provides new insights into the possible etiology of the neurodevelopmental impairments observed in ZC4H2-associated syndromes.

Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression

Sonic hedgehog (Shh) signaling is essential for the proliferation of cerebellar granule neuron progenitors (CGNPs), and its misregulation is linked to various disorders, including cerebellar cancer medulloblastoma (MB). During vertebrate neural development, RNF220, a ubiquitin E3 ligase, is involved in spinal cord patterning by modulating the subcellular location of glioma-associated oncogene homologs (Glis) through ubiquitination. RNF220 is also required for full activation of Shh signaling during cerebellum development in an epigenetic manner through targeting embryonic ectoderm development. ZC4H2 was reported to be involved in spinal cord patterning by acting as an RNF220 stabilizer. Here, we provided evidence to show that ZC4H2 is also required for full activation of Shh signaling in CGNP and MB progression by stabilizing RNF220. In addition, we found that the ubiquitin E3 ligase RING finger LIM domain-binding protein (RLIM) is responsible for ZC4H2 stabilization via direct ubiquitination, through which RNF220 is also thus stabilized. RLIM is a direct target of Shh signaling and is also required for full activation of Shh signaling in CGNP and MB cell proliferation. We further provided clinical evidence to show that the RLIM‒ZC4H2‒RNF220 cascade is involved in Shh-group MB progression. Disease-causative human RLIM and ZC4H2 mutations affect their interaction and regulation. Therefore, our study sheds light on the regulation of Shh signaling during cerebellar development and MB progression and provides insights into neural disorders caused by RLIM or ZC4H2 mutations.

Haploinsufficiency oftheTDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse

TDP43 pathology is seen in a large majority of amyotrophic lateral sclerosis(ALS)cases,suggesting a central pathogenic role of this regulatory protein.Clarifying the molecular mechanism controlling TDP43 stability and subcellular location might provide important insights into ALS therapy.The ubiquitin E3 ligase RNF220 is involved in different neural developmental processes through various molecular targets in the mouse.Here,we report that the RNF2207 mice showed progressively decreasing mobility to different extents,some of which developed typical ALS pathological characteristics in spinal motor neurons,including TDP43 cytoplasmic accumulation,atrocytosis,muscle denervation,and atrophy.Mechanistically,RNF220 interacts with TDP43 in vitro and in vivo and promotes its polyubiquitination and proteasomal degradation.In conclusion,we propose that RNF220 might be a modifier of TDP43 function in vivo and contribute to TDP43 pathology in neurodegenerative disease like ALS.