Biology subjects

Gingrich, E. C.

Publications and source records attributed to Gingrich, E. C..

3 recordsLinked to original sources

bioRxiv2025

Ten3-Lphn2-mediated target selection across the extended hippocampal network demonstrates a repeated strategy for circuit assembly

How do thousands of cell-surface proteins specify billions of neuronal connections in developing brains? We previously found that inverse expression of a ligand-receptor pair, teneurin-3 (Ten3) and latrophilin-2 (Lphn2) in CA1 and subiculum, instructs CA1[->]subiculum target selection through Ten3-Ten3 homophilic attraction and Ten3-Lphn2 heterophilic reciprocal repulsions. Here, we leveraged conditional knockouts to demonstrate that these mechanisms generalize to extended hippocampal networks, including entorhinal cortex and hypothalamus. Cooperation between attraction and repulsion differs depending on the order in which developing axons encounter the attractant and repellent subfields. Ten3 and Lphn2 can serve both as ligands for incoming axons and receptors for their own target selection, within the same neuron; Ten3 can be repulsive or attractive as ligand or receptor. Thus, multifunctionality and repeated use, together with recurrent circuit motifs prevalent in the brain, enable one ligand-receptor pair to instruct target selection of many more neurons.

neuroscience↗

bioRxiv2020

Latrophilin-2 repels Teneurin-3+ hippocampal axons during target selection

Parallel information processing is a salient feature of complex nervous systems. For example, the medial and lateral hippocampal networks (MHN and LHN) preferentially process spatial- and object-related information, respectively. However, the mechanisms underlying parallel network assembly during development remain largely unknown. Here, we show that complementary expression of cell-surface molecules Teneurin-3 (Ten3) and Latrophilin-2 (Lphn2) in the MHN and LHN, respectively, guides the precise assembly of both the MHN and LHN. Viral-genetic perturbations in vivo demonstrate that Ten3+ axons are repelled by target-derived Lphn2, revealing that Lphn2/Ten3-mediated repulsion and Ten3/Ten3-mediated attraction cooperate to control precise target selection of MHN axons. In the LHN, Lphn2+ axons are confined to Lphn2+ targets via repulsion from Ten3+ targets. Our findings demonstrate that assembly of parallel hippocampal networks follows a Ten3[->]Ten3, Lphn2[->]Lphn2 rule instructed by reciprocal repulsions.

neuroscience↗

bioRxiv2018

FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

The localization and translation of mRNAs is controlled by a diverse array of ribonucleoprotein particles (RNPs), multimolecular complexes containing mRNAs and RNA binding proteins. Fragile X granules (FXGs) are a family of RNPs that exemplify the diversity of RNA granules in the mammalian nervous system. FXGs are found in a conserved subset of neurons, where they localize exclusively to the axonal compartment. Notably, the specific RNA binding proteins and mRNAs found in FXGs depend on brain circuit and neuron type, with all forebrain FXGs containing Fragile X mental retardation protein (FMRP), the protein mutated in the human autism-related disorder Fragile X syndrome. FMRP negatively regulates FXG abundance but is not required for their association with ribosomes or mRNA. To better understand the circuit-dependent mechanisms whereby FMRP associates with and regulates FXGs, we asked how a disease-causing point mutation, I304N, in the KH2 RNA binding domain of FMRP affects these granules in two brain regions - cortex and hippocampus. We found that FMRPI304N had a reduced association with FXGs, as it was absent from approximately half of FXGs in cortex and nearly all FXGs in hippocampus. FXG abundance correlated with the number of FMRP-containing FXGs, suggesting that FMRP regulates FXG abundance by KH2-independent mechanisms that occur locally within the granules. Together, these findings illustrate that cell type-dependent mechanisms guide the assembly of similar RNA granules. Further, point mutations in RNA granule components may lead to cell type-dependent phenotypes that produce atypical forms of disorders that normally arise from more severe mutations.

neuroscience↗