Zc4h2, encoding a C4H2 type zinc-finger nuclear factor, is involved in multiple neural developmental processes. It functions as a co-factor for RNF220, an ubiquitin E3 ligase, and participates in pathways like Shh/Gli signaling, BMP signaling, and is crucial for noradrenergic neuron development [1,2,4].

In gene knockout studies, loss of either Zc4h2 or Rnf220 in mouse models disrupts the development of central noradrenergic neurons, as genes associated with these neurons are not properly maintained at later embryonic stages [1]. In both mouse and zebrafish, Zc4h2 knockout phenocopies RNF220 knockout in spinal patterning, with mispatterned progenitor and neuronal domains in the ventral spinal cord. Zc4h2 is required for RNF220 stability and proper Gli ubiquitination and signaling in vivo [2]. Loss of Zc4h2 in mouse embryonic cortex-derived neural stem cells (NSCs) inhibits their proliferation and promotes differentiation, likely through the up-regulation of Cend1 [3]. In zebrafish, zc4h2 knockout leads to abnormal swimming, increased twitching, and a reduction in GABAergic interneurons [5]. In mice, Zc4h2 knockout causes neonatal-lethality, reduced long-bone calcification, and upon postnatal induced loss, an osteoporosis-like phenotype with enhanced osteoclast differentiation [6].

In summary, Zc4h2 is essential for neural development, including noradrenergic neuron development, spinal cord patterning, and neural stem cell regulation. It also plays a role in bone development. Gene knockout models in mice and zebrafish have been instrumental in revealing these functions, and understanding Zc4h2 may provide insights into related neurodevelopmental and bone-related disorders [1,2,3,5,6].