NELL2, short for neural epidermal growth factor-like-like 2, is a secreted glycoprotein involved in multiple biological functions. It participates in signaling pathways such as those related to axon guidance, cell growth regulation, and sperm maturation. It has been linked to various biological processes including neuronal development, cancer cell proliferation, and male fertility, highlighting its overall biological importance. Genetic models, especially knockout mouse models, have been crucial in studying its functions [1-6, 8-10].

In male mice with Nell2 knocked out, they were infertile. This reveals that NELL2-mediated lumicrine signaling through OVCH2 is essential for male fertility as it regulates the differentiation of the initial segment of the caput epididymis and processing of sperm-related proteins [3]. In Ewing sarcoma cells, NELL2-cdc42 signaling inhibits cdc42, upregulates BAF complexes and EWS-FLI1 transcriptional output, and promotes cell proliferation. The identification of NELL2-high and NELL2-low populations in Ewing sarcoma further demonstrates its role in this cancer [1]. In hippocampal neurons, knockdown of NELL2 expression led to deterioration of neuronal development, including inhibited development progression, decreased axon growth, and increased axon branching, indicating its importance in neuronal polarization and axon growth [2].

In conclusion, NELL2 is a multifunctional gene involved in key biological processes such as neuronal development, male fertility, and cancer cell growth. Gene-knockout mouse models have been instrumental in revealing its role in male infertility and Ewing sarcoma, among others. These findings contribute to a better understanding of the underlying mechanisms of these biological processes and disease conditions, potentially paving the way for new therapeutic strategies.