Cellular Retinoic Acid Binding Protein 1 (CRABP1) is a key mediator of non-canonical activities of retinoic acid (RA). It forms complexes with specific signaling molecules like MAPK and CaMKII, functioning as RA-regulated signalsomes in a cell-context-dependent manner. These complexes are involved in multiple pathways, impacting stem cell proliferation, cancers, adipocyte health, neuro-immune regulation, heart and motor neuron diseases [1].

Gene knockout studies, especially using Crabp1 knockout (CKO) mice, have been crucial in understanding its functions. CKO mice exhibit an adult-onset ALS-like phenotype with deteriorated neuromuscular junctions, indicating CRABP1's role in maintaining neuromuscular junction integrity through the CRABP1-CaMKII-Agrn signaling pathway [3]. They also show altered exosome profiles, suggesting a novel function of CRABP1 in modulating exosome secretion and potentially intercellular communication [2]. In the heart, CKO mice have elevated basal CaMKII phosphorylation, leading to increased susceptibility to isoproterenol-induced acute and chronic cardiac injury, demonstrating CRABP1's protective role against such injuries by regulating CaMKII activity [6]. CKO mice also display reduced anxiety-like behaviors, altered HPA axis feedback inhibition, and reduced FKBP5 expression, highlighting CRABP1's role in HPA axis homeostasis [4]. Ablation of ARCCRABP1 neurons (neurons expressing CRABP1 in the arcuate nucleus) in mice results in obesity and a diabetic phenotype, showing its role in energy homeostasis regulation [5].

In summary, CRABP1 plays essential roles in various biological processes, including neuromuscular junction maintenance, exosome secretion, cardiac protection, HPA axis regulation, and energy homeostasis. Studies using CKO mouse models have significantly contributed to understanding its functions in relation to motor neuron diseases, heart diseases, stress-related disorders, and metabolic diseases.

References:

1. Nhieu, Jennifer, Lin, Yu-Lung, Wei, Li-Na. 2022. CRABP1 in Non-Canonical Activities of Retinoic Acid in Health and Diseases. In Nutrients, 14, . doi:10.3390/nu14071528. https://pubmed.ncbi.nlm.nih.gov/35406141/

2. Nhieu, Jennifer, Wei, Chin-Wen, Ludwig, Megan, Drake, Justin M, Wei, Li-Na. 2024. CRABP1-complexes in exosome secretion. In Cell communication and signaling : CCS, 22, 381. doi:10.1186/s12964-024-01749-w. https://pubmed.ncbi.nlm.nih.gov/39075476/

3. Lin, Yu-Lung, Nhieu, Jennifer, Liu, Pei-Yao, Lowe, Dawn, Wei, Li-Na. 2022. CRABP1-CaMKII-Agrn regulates the maintenance of neuromuscular junction in spinal motor neuron. In Cell death and differentiation, 29, 1744-1756. doi:10.1038/s41418-022-00959-4. https://pubmed.ncbi.nlm.nih.gov/35217789/

4. Lin, Yu-Lung, Wei, Chin-Wen, Lerdall, Thomas A, Nhieu, Jennifer, Wei, Li-Na. 2021. Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression. In International journal of molecular sciences, 22, . doi:10.3390/ijms222212240. https://pubmed.ncbi.nlm.nih.gov/34830120/

5. Yan, Lihong, Zhang, Xin, Jin, Liling, Liu, An, Li, Juxue. 2025. The ARCCRABP1 neurons play a crucial role in the regulation of energy homeostasis. In Nature communications, 16, 2319. doi:10.1038/s41467-025-57411-7. https://pubmed.ncbi.nlm.nih.gov/40057489/

6. Park, Sung Wook, Persaud, Shawna D, Ogokeh, Stanislas, Townsend, DeWayne, Wei, Li-Na. 2018. CRABP1 protects the heart from isoproterenol-induced acute and chronic remodeling. In The Journal of endocrinology, 236, 151-165. doi:10.1530/JOE-17-0613. https://pubmed.ncbi.nlm.nih.gov/29371236/