Cerebellin-1 (CBLN1) is a 35 kDa secreted glycoprotein in the Cerebellin family of TNF superfamily molecules (1). Cerebellins contain an N‑terminal collagenous domain and a C-terminal TNF/C1q-like domain. Mature human Cerebellin-1 shares 100% aa sequence identity with mouse and rat Cerebellin-1. It is expressed in the cerebellum, the parafascicular nucleus of the thalamus, and in the adrenal cortex and pancreatic islets (2 - 5). Cerebellin-1 forms noncovalent homotrimers that are disulfide-linked into hexamers (6). It can also form hetero-oligomers with Cerebellins-2, -3, and -4 and is required for the secretion of Cerebellin-3 (7 - 9). Cerebellin-1 is subject to proteolysis which can liberate 15-mer or 16-mer bioactive peptides from the C1q domain or remove the regions necessary for trimer or hexamer formation (6). Formation of the hexamer is required for Cerebellin-1’s ability to bind to synaptic structures (9, 10). It binds to postsynaptic densities through direct interactions with the glutamate receptor subunit GluRδ2 and to presynaptic membranes through direct interactions with alpha and beta Neurexins that contain the SS4 insert (11 - 14). The trans-synaptic trimolecular complex of GluRδ2, Cerebellin-1, and Neurexin promotes both presynaptic and postsynaptic development (11, 12). Cerebellin-1 itself is required for synaptic development, maintenance, and function (10, 12 - 15). It can also be internalized by Purkinje cells following secretion by cerebellar granule cells (2, 8, 15). The 16-mer and 15-mer peptides derived from Cerebellin-1 exert multiple endocrine effects including promoting corticosteroid secretion by cortical adrenal cells, inhibiting glucose‑stimulated insulin secretion from pancreatic islets, promoting Neuropeptide Y secretion by the hypothalamus, and decreasing plasma thyroid stimulating hormone (TSH) levels (4, 5, 16).