FIBCD1 is a Conserved Receptor for Chondroitin Sulphate Proteoglycans of the Brain Extracellular Matrix and a Candidate Gene for a Complex Neurodevelopmental Disorder

Abstract

The brain extracellular matrix (ECM) is enriched in chondroitin sulphate proteoglycans (CSPGs) with variable sulphate modifications that intimately participate in brain maturation and function. Very little is known about how the changing biophysical properties of the CSPGs are signalled to neurons. 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). Cultured Fibcd1 knockout (KO) neurons lack phenotypic and transcriptomic responses to CSPG stimulation. 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. Likewise, neuronal specific knockdown of a Fibcd1 orthologue in flies results in neuronal morphological changes at the neuromuscular junctions and behavioural defects. 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. 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.

stAPAminer: Mining Spatial Patterns of Alternative Polyadenylation for Spatially Resolved Transcriptomic Studies

“…However, the layer-specific pattern obtained from the APA profile was more distinguishable. Fibcd1 has recently been recognized as an evolutionarily conserved component of the brain extracellular matrix that is associated with a complex neurodevelopmental disorder [53] . Notably, two other genes, Dhdh and Cep126 , were not detected in the gene–spot expression profile; however, they demonstrated layer-specific APA usage in OPL and ONL, respectively.…”

stAPAminer: Mining Spatial Patterns of Alternative Polyadenylation for Spatially Resolved Transcriptomic Studies

“…Additional, Fibcd1 , a known chitin-binding receptor of the innate immune system, shows glomerular layer (GL) specificity according to both gene expression profile and APA profile, however, the layer-specific pattern obtained from the APA profile was more distinguishable. Fibcd1 has recently been recognized as an evolutionarily conserved component of brain extracellular matrix, which is associated with a complex neurodevelopmental disorder [53]. Interestingly, another two genes, Dhdh and Cep126 , are not detected from the gene-spot expression profile, however, they show layer-specific APA usage on OPL and ONL, respectively.…”

“…Fibcd1 has recently been recognized as an evolutionarily conserved component of brain extracellular matrix, which is associated with a complex neurodevelopmental disorder [53].…”

Proteins secreted by brain arteriolar smooth muscle cells are instructive for neural development

“…Among these differentially expressed genes (DEGs) (Additional file 5: Table S2), we identified 260 upregulated genes in HBVSMC-CM-treated neurons, including Ngfr, Fibcd1, Cyp26b1, Slc6a4, and Serpine1. All these genes are commonly involved in neuron growth, survival, and central nervous system development, with damage to some of these genes resulting in impaired neurodevelopment or delayed neuronal maturation [16][17][18][19][20][21][22][23]. In contrast, genes that inhibit neuron maturation were downregulated after neuronal exposure to VSMC-CM, such as Sox10, which is a well-established transcription factor that inhibits neuron development [24] (Fig.…”