BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes and Regulates Astrocytic Development and Injury Response

Abstract

Astrocytes perform a wide array of physiological functions, including structural support, ion exchange, and neurotransmitter uptake. Despite this diversity, molecular markers that label subpopulations of astrocytes are limited, and mechanisms that generate distinct astrocyte subtypes remain unclear. Here we identified serine protease high temperature requirement A 1 (HtrA1), a bone morphogenetic protein 4 signaling regulated protein, as a novel marker of forebrain astrocytes, but not of neural stem cells, in adult mice of both sexes. Genetic deletion of HtrA1 during gliogenesis accelerates astrocyte differentiation. In addition, ablation of HtrA1 in cultured astrocytes leads to altered chondroitin sulfate proteoglycan expression and inhibition of neurite extension, along with elevated levels of transforming growth factor-β family proteins. Brain injury induces HtrA1 expression in reactive astrocytes, and loss of HtrA1 leads to an impairment in wound closure accompanied by increased proliferation of endothelial and immune cells. Our findings demonstrate that HtrA1 is differentially expressed in adult mouse forebrain astrocytes, and that HtrA1 plays important roles in astrocytic development and injury response. Astrocytes, an abundant cell type in the brain, perform a wide array of physiological functions. Although characterized as morphologically and functionally diverse, molecular markers that label astrocyte subtypes or signaling pathways that lead to their diversity remain limited. Here, after examining the expression profile of astrocytes generated in response to bone morphogenetic protein signaling, we identify high temperature requirement A 1 (HtrA1) as an astrocyte-specific marker that is differentially expressed in distinct adult mouse brain regions. HtrA1 is a serine protease that has been linked to cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a small blood vessel disease in humans. Understanding the role of HtrA1 during development and after injury will provide insights into how distinct astrocyte populations are generated and their unique roles in injury and disease.

Expression of genes encoding IGF1, IGF2, and IGFBPs in blood of obese adolescents with insulin resistance

“…It solubilizes protein fibrils and disintegrates the fibrillary core structure, allowing productive interaction of aggregated polypeptides with the active site for rapid degradation. It has also been shown that brain injury induces HTRA1 expression in reactive astrocytes, and loss of HTRA1 leads to an impairment in wound closure accompanied by increased proliferation of endothelial and immune cells (Chen et al 2018). It is possible that obesity and insulin resistance related down-regulation of HTRA1 participates in the development of some obesity complications.…”

Metabolic compartmentalization between astroglia and neurons in physiological and pathophysiological conditions of the neurovascular unit

“…[21][22][23] Now, the NVU is a tool that can be used to understand normal brain physiology as well as the pathophysiology of numerous neurological disorders. [24][25][26][27][28][29] Conversely, the malfunction of astroglia in the NVU (i.e., "astrogliopathy") [30][31][32][33][34] induces neuronal dysfunction, leading to various neurological disorders including cerebrovascular disease (e.g., stroke and small vessel disease-like Binswanger's disease and cerebral autosomaldominant arteriopathy with subcortical infarct and leukoencephalopathy [CADASIL]/ 35 cerebral autosomal recessive arteriopathy with subcortical infarct and leukoencephalopathy [CARASIL]), 36,37 neurodegenerative disease (e.g., Alzheimer's disease, 38,39 Parkinson's disease, 40,41 and amyotrophic lateral sclerosis [ALS]), [42][43][44] and neuroimmunological disease (e.g., multiple sclerosis [MS], [45][46][47][48] and neuromyelitis optica spectrum disorder [NMOSD]). 49,50 This review will focus on the supportive roles of astroglia in the NVU from the perspective of three major metabolic compartments with neurons: (i) glucose and lactate; (ii) fatty acid and ketone bodies (KBs); and (iii) D-and L-serine.…”

A Study of Icariin Modulating Hippocampal Neurogenesis in Depression Based on Quantitative CSF Proteomics

“…Down-expressed HtrA1 is related to a variety of neurological diseases. HtrA1 could mediate transforming growth factor-β hydrolysis and bone morphogenetic protein inhibition to prevent neural stem cell proliferation and differentiation inhibition [49]. In this study, the treatment of ICA reversed CUMSinduced Htra1 reduction in CSF, neurogenesis dysfunction and neuronal loss in DG, suggesting that the antihippocampal damage effect of ICA may be related to the regulation of Htra1 content in CSF.…”