LRR-Containing Oncofetal Trophoblast Glycoprotein 5T4 Shapes Neural Circuits in Olfactory and Visual Systems

Abstract

In mammals, the sensory experience can regulate the development of various brain structures, including the cortex, hippocampus, retina, and olfactory bulb (OB). Odor experience-evoked neural activity drives the development of dendrites on excitatory projection neurons in the OB, such as mitral and tufted cells, as well as inhibitory interneurons. OB interneurons are generated continuously in the subventricular zone and differentiate into granule cells (GCs) and periglomerular cells (PGCs). However, it remains unknown what role each type of OB interneuron plays in controlling olfactory behaviors. Recent studies showed that among the various types of OB interneurons, a subtype of GCs expressing oncofetal trophoblast glycoprotein 5T4 is required for simple odor detection and discrimination behaviors. Mouse 5T4 (also known as Tpbg) is a type I membrane glycoprotein whose extracellular domain contains seven leucine-rich repeats (LRRs) sandwiched between characteristic LRR-N and LRR-C regions. Recently, it was found that the developmental expression of 5T4 increases dramatically in the retina just before eye-opening. Single-cell transcriptomics further suggests that 5T4 is involved in the development and maintenance of functional synapses in a subset of retinal interneurons, including rod bipolar cells (RBCs) and amacrine cells (ACs). Collectively, 5T4, expressed in interneurons of the OB and retina, plays a key role in sensory processing in the olfactory and visual systems.

Identification of TPBG-Expressing Amacrine Cells in DAT-tdTomato Mouse

“… 30 It was suggested that TPBG played a potential role in visual system development before and after receiving light stimulus. 30 , 60 TPBG has also been reported to selectively label inner midget RGCs in the primate retina, suggesting the importance of this protein. 61 , 62 The expression pattern of Tpbg in ACs of mouse retina has been studied previously in two high-throughput scRNA-seq studies.…”

“…We also identified a new genetic marker Tpbg , which is involved in retinal development after birth. 60 The identification of Tpbg provides a powerful genetic handle for further study of the TH2 cells. We believe our study contains sufficient novel discoveries that can contribute to the field in the study of the function of ACs.…”

“…In the mouse retina, TPBG is mainly expressed in rod bipolar cells and an uncharacterized group of ACs. 60 According to studies about the relationship between TPBG and retina, TPBG expression is undetectable in the retina at birth until significant increase before eye opening. The expression of TPBG remained stable until postnatal 11 day and increased by approximately 10-fold by postnatal day 12.…”

Trophoblast glycoprotein is required for efficient synaptic vesicle exocytosis from retinal rod bipolar cells

“…In the retina, TPBG may also regulate RBC dendritic branching complexity in the OPL. TPBG is a known regulator of Wnt signaling (He et al, 2015; Kagermeier-Schenk et al, 2011), which is required for functional synaptic targeting and OPL lamination in RBCs, therefore TPBG may promote RBC dendritic development through control of the Wnt pathway (Tsuboi, 2020). We didn’t detect a structural or physiological phenotype in RBC dendrites, but thorough evaluation of RBC dendritic maturation and branching using sparse labeling techniques might reveal a more subtle effect of TPBG-KO on dendritic architecture.…”

Effects of nasal inflammation on the olfactory bulb

“…LPS administrations, the GL and EPL of the OB ipsilateral to the LPS-treated naris expresses significantly less vGluT1 compared to the contralateral OB or to saline-treated controls [21]. Similarly, expression of 5T4, a transmembrane glycoprotein uniquely expressed by GCs with dendrites projecting to the sEPL [74,75], is also significantly decreased throughout the sEPL of the OB ipsilateral to the LPS-treated naris after 3 weeks of administrations [21]. These data suggest that intrabulbar neural circuits may undergo synaptic pruning in response to COI in the form of decreased dendrodendritic synapses.…”