A Short Isoform of Coagulation Factor XII mRNA Is Expressed by Neurons in the Human Brain.

A Short Isoform of Coagulation Factor XII mRNA Is Expressed by Neurons in the Human Brain.

Publication date: Jun 07, 2019

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 has 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 (FXII). 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.

Zamolodchikov, D., Bai, Y., Tang, Y., , McWhirter, Macdonald, L.E., and Alessandri-Haber, N. A Short Isoform of Coagulation Factor XII mRNA Is Expressed by Neurons in the Human Brain. 18271. 2019 Neuroscience.

Concepts Keywords
Alzheimer AD multiple sclerosis
Brain Neurodevelopmental disorders
Catalytic Branches of biology
Cerebrospinal Fluid Coagulation system
Coagulation Anatomy
Hepatocyte Growth Factor Proteins
HGF Blood
Hybridization Kinin–kallikrein system
Isoform Contact activation system
Kallikrein Growth factors
Liver C-Met
Mice Hepatocyte growth factor
MRNA Prekallikrein
Multiple Sclerosis Neuroscience
Neurodegeneration Hybridization
Neurodevelopmental Disorders
Neurons
Pathology
Physiology
Proline
Pyramidal Neurons
Recombinant

Semantics

Type Source Name
disease MESH neurodevelopmental disorders
disease MESH development
gene UNIPROT RNMT
gene UNIPROT MET
gene UNIPROT SLTM
drug DRUGBANK Methionine
gene UNIPROT HGF
gene UNIPROT IL6
gene UNIPROT SOS1
gene UNIPROT KLK4
drug DRUGBANK Proline
disease DOID multiple sclerosis
disease MESH multiple sclerosis

Original Article

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