Parcellation of cerebellins 1, 2, and 4 among different subpopulations of dorsal horn neurons in mouse spinal cord

Abstract

The cerebellins (Cblns) are a family of secreted proteins that are widely expressed throughout the nervous system, but whose functions have been studied only in the cerebellum and striatum. Two members of the family, Cbln1 and Cbln2, bind to neurexins on presynaptic terminals and to GluR∂s postsynaptically, forming trans-synaptic triads that promote synapse formation. Cbln1 has a higher binding affinity for GluR∂s and exhibits greater synaptogenic activity than Cbln2. In contrast, Cbln4 does not form such triads and its function is unknown. The different properties of the three Cblns suggest that each plays a distinct role in synapse formation. To begin to elucidate Cbln function in other neuronal systems, we used in situ hybridization to examine Cbln expression in the mouse spinal cord. We find that neurons expressing Cblns 1, 2, and 4 tend to occupy different laminar positions within the dorsal spinal cord, and that Cbln expression is limited almost exclusively to excitatory neurons. Combined in situ hybridization and immunofluorescent staining shows that Cblns 1, 2, and 4 are expressed by largely distinct neuronal subpopulations, defined in part by sensory input, although there is some overlap and some individual neurons co-express two Cblns. Our results suggest that differences in connectivity between subpopulations of dorsal spinal cord neurons may be influenced by which Cbln each subpopulation contains. Competitive interactions between axon terminals may determine the number of synapses each forms in any given region, and thereby contribute to the development of precise patterns of connectivity in the dorsal gray matter.

Identification and quantification of neuropeptides in naïve mouse spinal cord using mass spectrometry reveals [des‐Ser1]‐cerebellin as a novel modulator of nociception

“…Our findings confirm the recent report demonstrating Cbln1 mRNA expression in mouse spinal cord by in situ hybridization (Cagle and Honig ). In 1984, Slemmon et al .…”

A transcription factor network specifying inhibitory versus excitatory neurons in the dorsal spinal cord

“…4A). This group also contains genes that code for factors, such as Cbln1 and Cbln2, which are involved in forming connections that promote synapse formation in glutamatergic neurons (Cagle and Honig, 2014;Ito-Ishida et al, 2012). Thus, genes activated by Ascl1, but repressed by Ptf1a, define a subset of excitatory neurons in the dorsal spinal cord (Fig.…”

Shaping Synapses by the Neural Extracellular Matrix

“…Cerebellins function as trans-synaptic linkers as they form tripartite complexes with the presynaptic neurexins or “deleted in colorectal cancer” (DCC) and the postsynaptic delta-type glutamate (GluD1 and GluD2) receptors (Ito-Ishida et al, 2008 ; Matsuda et al, 2010 ; Uemura et al, 2010 ; Lee et al, 2012 ; Wei et al, 2012 ; Haddick et al, 2014 ). In vertebrates, there are four cerebellins (Cbln1–4) that are widely expressed throughout the brain (Miura et al, 2006 ; Wei et al, 2012 ; Cagle and Honig, 2014 ; Seigneur and Südhof, 2017 ). Cbln1 and Cbln3 are mainly expressed in cerebellar granular cells (GCs) and Cbln2 and Cbln4 are heterogeneously expressed in the forebrain (Pang et al, 2000 ; Miura et al, 2006 ).…”