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 dystoni...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.展开更多
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...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.展开更多
基金the National Natural Science Foundation of China(31871483 and 31671521 to B.M.,31500847 to P.M.,31771134 to N.S.,81571332 and 91232724 to Y.D.,and 31671509 to D.S.)the National Key R&D Program of China(2017YFA0104002 to Y.-Q.D.)Shanghai Municipal Science and Technology Major Project(2018SHZDZX01)and ZJLab.
文摘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.
基金This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences(XDB13000000 to B.M.)the National Natural Science Foundation of China(32170965 to P.M.and 82060292 to S.Z.)+1 种基金Yunnan Basic Research Program(202001AS070036 to B.M.)the open project of State Key Laboratory of Genetic Resources and Evolution(GREKF20-07 to S.Z.and GREKF18-12 to Yan Li).P.M.was supported by the Youth Innovation Promotion Association of Chinese Academy of Sciences.
文摘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.
