A Short Isoform of Coagulation Factor XII mRNA Is Expressed by Neurons in the Human Brain
| Autor: | Nicole Alessandri-Haber, Macdonald Lynn, Yajun Tang, John Mcwhirter, Yu Bai, Daria Zamolodchikov |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Gene isoform Mice 129 Strain In situ hybridization Coagulation Factor XII Animals Genetically Modified 03 medical and health sciences 0302 clinical medicine RNA Isoforms medicine Animals RNA Messenger Cells Cultured Neurons Messenger RNA Hepatocyte Growth Factor Chemistry General Neuroscience Neurodegeneration Prekallikrein Brain Human brain Kallikrein medicine.disease Cell biology Mice Inbred C57BL 030104 developmental biology medicine.anatomical_structure Liver Factor XII Kallikreins 030217 neurology & neurosurgery |
| Zdroj: | Neuroscience. 413:294-307 |
| ISSN: | 0306-4522 |
| DOI: | 10.1016/j.neuroscience.2019.05.040 |
| Popis: | Coagulation factor XII (FXII) is synthesized in the liver and secreted into the circulation, where it initiates the contact activation system. Although typically thought to be restricted to the circulation, FXII protein has been found in the brain of Alzheimer's disease (AD) and multiple sclerosis patients. Moreover, activation of the contact system has been detected in the cerebrospinal fluid of these patients as well as in the brain of healthy and AD individuals. While FXII protein has been detected in the brain, its source and its potential role in brain physiology and/or pathology have not been elucidated. Using in situ hybridization, we show that a shorter FXII mRNA isoform is expressed by neurons in human brain and in the brain of FXII humanized mice, with the highest expression observed in pyramidal neurons. This shorter FXII transcript contains an open reading frame coding for the portion of FXII that spans its proline-rich and catalytic domains (FXII297-596). We show that a recombinant version of this shorter FXII protein is activated by plasma kallikrein, reciprocally activates prekallikrein, and converts pro-hepatocyte growth factor (HGF) to active HGF in vitro. HGF-Met signaling plays a role in neuronal development and survival, and its dysregulation has been implicated in neurodevelopmental disorders and neurodegeneration. Taken together, our results show that a short isoform of FXII mRNA is expressed in the brain and raise the possibility that brain-derived FXII may be involved in HGF-Met signaling in neurons. |
| Databáze: | OpenAIRE |
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