Esyt1, short for Extended Synaptotagmin 1, is a Ca2+-dependent mediator involved in endoplasmic reticulum-plasma membrane bridge formation [2,4]. It also functions as an ER resident SMP-domain protein. Esyt1 is crucial for multiple biological processes, participating in pathways related to lipid and calcium homeostasis, cell-cell signaling, and synaptic function [1,2,4]. Its role in these processes makes it biologically important for overall cellular and organismal homeostasis, and genetic models such as KO mouse models are valuable for studying its functions.

In KO or knockdown models, deletion of Esyt1 reduced the number and length of mitochondria-ER contact sites (MERCs), impaired ER to mitochondria calcium flux, and altered the mitochondrial lipidome, highlighting its role in mitochondrial and cellular homeostasis [1]. In glioblastoma, Esyt1 knockdown or knockout increased GPR133 signaling and slowed tumor growth, suggesting its tumorigenic functions [2,4]. In a mouse model of ALS, down-regulation of Esyt1 in V1 interneurons was observed, and V1 restricted overexpression of Esyt1 rescued inhibitory synapses, increased motor neuron survival, and ameliorated motor phenotypes [3].

In conclusion, Esyt1 plays essential roles in mitochondrial lipid and calcium homeostasis, regulation of GPR133 signaling in glioblastoma, and stabilization of V1 interneuron-motor neuron connectivity in ALS. The use of KO or knockdown mouse models has been instrumental in uncovering these functions, contributing to our understanding of these disease areas and potentially guiding future therapeutic strategies.

References:

1. Janer, Alexandre, Morris, Jordan L, Krols, Michiel, Prudent, Julien, Shoubridge, Eric A. 2023. ESYT1 tethers the ER to mitochondria and is required for mitochondrial lipid and calcium homeostasis. In Life science alliance, 7, . doi:10.26508/lsa.202302335. https://pubmed.ncbi.nlm.nih.gov/37931956/

2. Stephan, Gabriele, Haddock, Sara, Wang, Shuai, Neubert, Thomas A, Placantonakis, Dimitris G. 2024. Modulation of GPR133 (ADGRD1) signaling by its intracellular interaction partner extended synaptotagmin 1. In Cell reports, 43, 114229. doi:10.1016/j.celrep.2024.114229. https://pubmed.ncbi.nlm.nih.gov/38758649/

3. Mora, Santiago, Stuckert, Anna, von Huth Friis, Rasmus, Verhaagen, Joost, Allodi, Ilary. 2024. Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS. In Nature communications, 15, 4867. doi:10.1038/s41467-024-48925-7. https://pubmed.ncbi.nlm.nih.gov/38849367/

4. Stephan, Gabriele, Erdjument-Bromage, Hediye, Liu, Wenke, Neubert, Thomas, Placantonakis, Dimitris G. 2023. Modulation of GPR133 (ADGRD1) Signaling by its Intracellular Interaction Partner Extended Synaptotagmin 1 (ESYT1). In bioRxiv : the preprint server for biology, , . doi:10.1101/2023.02.09.527921. https://pubmed.ncbi.nlm.nih.gov/36798364/