To date, associations between disruptions to proteoglycan receptor function and human disease have not been reported. Whether CNTN1 or RAGE brain functions are linked to CS-4,6S recognition and the role of CS-4,6S in the brain is poorly understood. RAGE is also associated with Alzheimer pathology 17. For example, CS-4,6S (or CS-E) recognition was reported for Contactin-1 (CNTN1) and in the lungs for Receptor for Advanced Glycation End Products (RAGE) 15, 16. Less is known regarding recognition of specifically sulphated GAGs on CSPGs. Receptor Protein Tyrosine Phosphatase sigma (PTPσ) and its subfamily member Leukocyte Common Antigen-Related (LAR), as well as the Nogo receptor family members, Nogo66 receptor–1 and 3 (NgR1 and 3) were demonstrated to bind CSPGs 12– 14, however, their role in the brain is unclear. This includes closure of the ‘critical period’ of heightened synaptic plasticity, when CSPGs condense into lattice-like structures around neurons, known as peri-neuronal nets (PNNs), which restrict juvenile synaptic plasticity and participate in memory formation, retention and extinction 1, 10, 11.įew cell-surface receptors for CSPGs have been identified. Different spatiotemporal distributions of CSPGs with variable sulphate modifications correlate with specific and discrete developmental stages as part of the dramatic reorganisation of the ECM that accompanies and regulates brain maturation 2, 8, 9. A seminal GAG is chondroitin sulphate (CS), a component of chondroitin sulphate proteoglycans (CSPGs).
Proteoglycans are composed of negatively charged glycosaminoglycans (GAGs), which consists of repeating disaccharide units, covalently joined to a core protein. Additional connections have been made between altered glycosylation, ECM composition and autism spectrum disorder (ASD), but the molecular mechanisms remain poorly understood 7. While multiple systems are often affected, most disorders also involve the central nervous system (CNS), with accompanying symptoms including congenital malformations, epilepsy, intellectual disability and developmental delay 5, 6. There are many inherited human disorders caused by disruptions to the glycosylation pathways. Glycans coordinate and are essential for many neurodevelopmental processes, including axon outgrowth and guidance, synaptogenesis, migration and synaptic plasticity 2– 4. The ECM is structurally heterogenous and is composed primarily of glycans and glycoconjugates (proteoglycans, glycoproteins and glycolipids). The brain extracellular matrix (ECM) is a dynamic microenvironment that plays a critical role in the development and maintenance of the nervous system 1, 2. Taken together, our results demonstrate that FIBCD1 is a novel, evolutionarily conserved component of ECM sulphation recognition that is crucial for neuronal development and function. Finally, we report two undiagnosed patients with a complex neurodevelopmental disorder with deleterious variants in FIBCD1, strongly implicating FIBCD1 in the development of the disease. Likewise, neuronal specific knockdown of a Fibcd1 orthologue in flies results in neuronal morphological changes at the neuromuscular junctions and behavioural defects. Further, Fibcd1 KO mice exhibit accumulation of CS-4S, likely resulting in deficits of hippocampal-dependent learning tasks and abrogated synaptic remodelling, a phenotype rescued by enzymatic digestion of CSPGs. Cultured Fibcd1 knockout (KO) neurons lack phenotypic and transcriptomic responses to CSPG stimulation. Here, we report Fibrinogen C Domain Containing 1 (FIBCD1), a known chitin-binding receptor of the innate immune system, to be highly expressed in the hippocampus and to specifically bind CSPGs containing 4-O sulphate modification (CS-4S).
Very little is known about how the changing biophysical properties of the CSPGs are signalled to neurons.
The brain extracellular matrix (ECM) is enriched in chondroitin sulphate proteoglycans (CSPGs) with variable sulphate modifications that intimately participate in brain maturation and function.
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