MiR99a is a microRNA that plays diverse roles in biological processes and disease conditions. It is part of the evolutionarily conserved miR-99 family, which also includes miR-99b and miR-100. MiR99a has been implicated in regulating multiple cellular functions, and is associated with pathways like PI3k/Akt and ERK/MAPK [1]. It is of great biological importance as it impacts various physiological and pathological states.

In Kaposi's sarcoma, miR99a inhibits MMP7 and MMP13 through the PI3k/Akt and ERK/MAPK signaling pathways respectively, regulating the invasiveness of the tumor [1]. In ischemic stroke, exosomal circCNOT6L attenuates astrocyte apoptotic signals via the miR99a-5p/SERPINE1 axis, alleviating injury [2]. In inflammatory dilated cardiomyopathy, low-intensity pulsed ultrasound increases the secretion of extracellular vesicles selectively loaded with miR-99a, which suppresses mTOR and TRIB2 expression in CD4+ T cells to modulate cellular differentiation and protect against disease progression [3]. In skeletal muscle, MR signaling mediates diet-induced reduction of miR-99a, which negatively targets CD36, and abnormal miR-99a expression affects lipid content, mitochondria function, and insulin sensitivity [4]. In macrophage polarization, miR-99a is among the miRNAs that regulate this process, which has significance in immune disorders and cancer [5]. In Down syndrome, miR-99a is overexpressed, potentially contributing to associated neuropathology, congenital heart defects, leukemia, and low solid tumor development rates [6]. In childhood acute lymphoblastic leukemia, underexpression of miR-99a could be a marker for bad prognosis [7]. In major depressive disorder, miR-99a is involved in the regulation of synaptic plasticity [8].

In conclusion, miR99a is a multifunctional microRNA involved in various biological processes and diseases. Studies using different models, though not specifically KO/CKO mouse models in the provided references, have revealed its role in regulating tumor invasiveness, cell apoptosis, immune cell differentiation, lipid metabolism, macrophage polarization, and synaptic plasticity. Understanding miR99a's functions provides insights into disease mechanisms and potential therapeutic targets for diseases such as Kaposi's sarcoma, ischemic stroke, inflammatory dilated cardiomyopathy, metabolic disorders, immune-related diseases, and neuropsychiatric conditions.

References:

1. Zhang, Jun, Wang, Shan, Lu, Linya, Wei, GuangHui. 2014. MiR99a modulates MMP7 and MMP13 to regulate invasiveness of Kaposi's sarcoma. In Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, 35, 12567-73. doi:10.1007/s13277-014-2577-6. https://pubmed.ncbi.nlm.nih.gov/25234715/

2. He, Wanting, Gu, Lian, Yang, Jialei, Nan, Aruo, Su, Li. 2023. Exosomal circCNOT6L Regulates Astrocyte Apoptotic Signals Induced by Hypoxia Exposure Through miR99a-5p/SERPINE1 and Alleviates Ischemic Stroke Injury. In Molecular neurobiology, 60, 7118-7135. doi:10.1007/s12035-023-03518-1. https://pubmed.ncbi.nlm.nih.gov/37531026/

3. Sun, Ping, Li, Yi, Li, Yifei, Zhang, Maomao, Tian, Jiawei. . Low-intensity pulsed ultrasound protects from inflammatory dilated cardiomyopathy through inciting extracellular vesicles. In Cardiovascular research, 120, 1177-1190. doi:10.1093/cvr/cvae096. https://pubmed.ncbi.nlm.nih.gov/38696702/

4. Hulse, Jack L, Habibi, Javad, Igbekele, Aderonke E, Sowers, James R, Jia, Guanghong. . Mineralocorticoid Receptors Mediate Diet-Induced Lipid Infiltration of Skeletal Muscle and Insulin Resistance. In Endocrinology, 163, . doi:10.1210/endocr/bqac145. https://pubmed.ncbi.nlm.nih.gov/36039677/

5. Ghafouri-Fard, Soudeh, Abak, Atefe, Tavakkoli Avval, Shamim, Taheri, Mohammad, Samadian, Mohammad. 2021. The impact of non-coding RNAs on macrophage polarization. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 142, 112112. doi:10.1016/j.biopha.2021.112112. https://pubmed.ncbi.nlm.nih.gov/34449319/

6. Brás, Aldina, Rodrigues, António S, Gomes, Bruno, Rueff, José. 2017. Down syndrome and microRNAs. In Biomedical reports, 8, 11-16. doi:10.3892/br.2017.1019. https://pubmed.ncbi.nlm.nih.gov/29403643/

7. Gutierrez-Camino, Angela, Garcia-Obregon, Susana, Lopez-Lopez, Elixabet, Astigarraga, Itziar, Garcia-Orad, Africa. 2019. miRNA deregulation in childhood acute lymphoblastic leukemia: a systematic review. In Epigenomics, 12, 69-80. doi:10.2217/epi-2019-0154. https://pubmed.ncbi.nlm.nih.gov/31833405/

8. Rahmani, Shayan, Kadkhoda, Sepideh, Ghafouri-Fard, Soudeh. 2022. Synaptic plasticity and depression: the role of miRNAs dysregulation. In Molecular biology reports, 49, 9759-9765. doi:10.1007/s11033-022-07461-7. https://pubmed.ncbi.nlm.nih.gov/35441941/