CRLF3 (cytokine receptor-like factor 3) is an evolutionarily conserved orphan cytokine receptor that primarily functions in neuroprotection and hematopoiesis 1. The protein contains a fibronectin type 3 domain with a WSXWS motif characteristic of class I cytokine receptors and a SPRY domain for protein-protein interactions 1. CRLF3 serves as a neuroprotective receptor for erythropoietin (Epo) and its splice variant EV-3, mediating anti-apoptotic mechanisms in neurons 23. In neuronal contexts, CRLF3 regulates neuronal maturation and dendrite formation, with loss-of-function variants causing impaired synaptic function and reduced firing rates 4. The receptor also plays a critical role in platelet production by regulating the final stage of platelet genesis through microtubule stability control via interactions with Hippo pathway members 5. CRLF3 deficiency results in sustained thrombocytopenia without affecting other blood cell lineages 5. Disease relevance includes associations with neurodevelopmental disorders, as the L389P variant increases autism burden in NF1 patients 4, and potential therapeutic targeting for thrombocythemia treatment 5. The receptor is absent in species lacking traditional nervous systems but present across eumetazoans, suggesting its emergence coincided with nervous system evolution 3.