The Secreted Protein C1QL1 and Its Receptor BAI3 Control the Synaptic Connectivity of Excitatory Inputs Converging on Cerebellar Purkinje Cells

Abstract

Precise patterns of connectivity are established by different types of afferents on a given target neuron, leading to well-defined and non-overlapping synaptic territories. What regulates the specific characteristics of each type of synapse, in terms of number, morphology, and subcellular localization, remains to be understood. Here, we show that the signaling pathway formed by the secreted complement C1Q-related protein C1QL1 and its receptor, the adhesion-GPCR brain angiogenesis inhibitor 3 (BAI3), controls the stereotyped pattern of connectivity established by excitatory afferents on cerebellar Purkinje cells. The BAI3 receptor modulates synaptogenesis of both parallel fiber and climbing fiber afferents. The restricted and timely expression of its ligand C1QL1 in inferior olivary neurons ensures the establishment of the proper synaptic territory for climbing fibers. Given the broad expression of C1QL and BAI proteins in the developing mouse brain, our study reveals a general mechanism contributing to the formation of a functional brain.

Expression patterns of C1ql4 and its cell‐adhesion GPCR Bai3 in the murine testis and functional roles in steroidogenesis

“…To date, the biologic effects of C1ql4 have been restricted to its ability to inhibit adipocyte differentiation by decreasing ERK1/2 activation (4), to stimulate angiogenesis through activation of the ERK1/2 signal pathway (9), and to control myoblast fusion (7). The C1QL4 putative receptor BAI3 was reported to be restricted in brain regions (such as the hippocampus, cerebral cortex, cerebellum, and neurons), vascular endothelial cells, and myoblasts cells and involved in neural regulation, angiogenesis, and myoblast fusion (2, 7, 9, 17, 24–26). To the best of our knowledge, we revealed a previously unidentified distribution and function of C1ql4 and Bai3 in the testis, which unveiled the putative role of C1QL4 and BAI3 as novel regulators of gonadal function in rodents.…”

Expression of C1ql3 in Discrete Neuronal Populations Controls Efferent Synapse Numbers and Diverse Behaviors

“…Recent papers investigating the cerebellum concluded that presynaptically secreted C1ql1 from the inferior olive climbing fibers interacts with postsynaptic BAI3 on Purkinje cells, and that this interaction promotes synapse maturation (Kakegawa et al, 2015; Sigoillot et al, 2015). Whether the mechanism of C1ql’s influence on synapses is similar across family members remains to be determined, although C1ql1 and C1ql3 have similar affinities for BAI3 (Bolliger et al, 2011).…”

“…Our initial experiments suggested that C1ql’s may function in synapse elimination and/or maintenance (Bolliger et al, 2011), and elegant recent studies confirmed a synaptic role for C1ql1 in the cerebellum (Kakegawa et al, 2015; Sigoillot et al, 2015). Furthermore, we identified C1ql proteins as high-affinity ligands for BAI3 (renamed ADGRB3 (Hamann et al, 2015)), an adhesion-class GPCR, which was validated as a C1ql1 receptor in cerebellum (Bolliger et al, 2011; Kakegawa et al, 2015).…”

Synaptic Neurexin Complexes: A Molecular Code for the Logic of Neural Circuits

“…Subsequent pioneering in vivo experiments revealed that postsynaptic BAI3 physiologically functions as a C1ql1 receptor in climbing-fiber synapses in cerebellum, and that deletion of either BAI3 or C1ql1 causes a loss of climbing-fiber synapses (Kakegawa et al, 2015; Sigoillot et al, 2015), proving a role for C1ql’s in synapse formation. Similarly, C1ql3 deletion from amygdala neurons was shown to suppress the number of synapses formed by C1ql3-expressing amygdala neuron on prefrontal cortex neurons, confirming a synaptic role for C1ql’s (Martinelli et al, 2016).…”