Cerebrospinal fluid is a clear fluid that occupies the ventricular and subarachnoid spaces within and around the brain and spinal cord. Cerebrospinal fluid is a dynamic signaling milieu that transports nutrients, waste materials and neuroactive substances that are crucial for the development, homeostasis and functionality of the central nervous system. The mechanisms that enable cerebrospinal fluid to simultaneously exert these homeostatic/dynamic functions are not fully understood. SCO-spondin is a large glycoprotein secreted since the early stages of development into the cerebrospinal fluid. Its domain architecture resembles a combination of a matricellular protein and the ligand-binding region of LDL receptor family. The matricellular proteins are a group of extracellular proteins with the capacity to interact with different molecules, such as growth factors, cytokines and cellular receptors; enabling the integration of information to modulate various physiological and pathological processes. In the same way, the LDL receptor family interacts with many ligands, including β-amyloid peptide and different growth factors. The domains similarity suggests that SCO-spondin is a matricellular protein enabled to bind, modulate, and transport different cerebrospinal fluid molecules. SCO-spondin can be found soluble or polymerized into a dynamic threadlike structure called the Reissner fiber, which extends from the diencephalon to the caudal tip of the spinal cord. Reissner fiber continuously moves caudally as new SCO-spondin molecules are added at the cephalic end and are disaggregated at the caudal end. This movement, like a conveyor belt, allows the transport of the bound molecules, thereby increasing their lifespan and action radius. The binding of SCO-spondin to some relevant molecules has already been reported; however, in this review we suggest more than 30 possible binding partners, including peptide β-amyloid and several growth factors. This new perspective characterizes SCO-spondin as a regulator of cerebrospinal fluid activity, explaining its high evolutionary conservation, its apparent multifunctionality, and the lethality or severe malformations, such as hydrocephalus and curved body axis, of knockout embryos. Understanding the regulation and identifying binding partners of SCO-spondin are crucial for better comprehension of cerebrospinal fluid physiology.

Hypothalamic tanycytes have traditionally been viewed as metabolic sensors, structural components of hypothalamic barriers, and transporters of circulating signals. However, accumulating evidence indicates that they also translate metabolic, hormonal, and inflammatory inputs into bioactive signals that coordinate communication with neurons, glia, blood vessels, and cerebrospinal fluid. Here, we introduce the term tanykines to describe bioactive molecules whose extracellular availability depends on their regulated generation, release, processing, or bioactivation by tanycytes and that modify tanycyte function or other target cells. We propose a mechanism-based taxonomy comprising: (i) primary tanykines, directly generated and released by tanycytes, including ATP, lactate, β-hydroxybutyrate, prostaglandin E₂, and VEGF-A; (ii) secondary processed tanykines, generated extracellularly from a primary tanykine, exemplified by ATP-derived adenosine; and (iii) bioactivated tanykines, produced through tanycyte-dependent transformation of a transported precursor, exemplified by T4-to-T3 conversion. We further distinguish established, probable, and candidate or disputed tanykines according to tanycytic origin, regulated extracellular availability, target-cell identity, mechanism of action, and physiological causality. This framework separates tanykines from molecules merely sensed, transported, or expressed by tanycytes and reframes these cells as context-dependent signal generators coordinating metabolic and neuroendocrine homeostasis.