Abstract
The High Mobility Group Box 1 (HMGB1) is the most abundant nuclear nonhistone protein that is involved in transcription regulation. In addition, HMGB1 has previously been found as an extracellularly acting protein enhancing neurite outgrowth in cultured neurons. Although HMGB1 is widely expressed in the developing central nervous system of vertebrates and invertebrates, its function in the developing mouse brain is poorly understood. Here, we have analyzed developmental defects of the HMGB1 null mouse forebrain, and further examined our findings in ex vivo brain cell cultures. We find that HMGB1 is required for the proliferation and differentiation of neuronal stem cells/progenitor cells. Enhanced apoptosis is also found in the neuronal cells lacking HMGB1. Moreover, HMGB1 depletion disrupts Wnt/β-catenin signaling and the expression of transcription factors in the developing cortex, including Foxg1, Tbr2, Emx2, and Lhx6. Finally, HMGB1 null mice display aberrant expression of CXCL12/CXCR4 and reduced RAGE signaling. In conclusion, HMGB1 plays a critical role in mammalian neurogenesis and brain development.
Highlights
The High Mobility Group Box 1 protein (HMGB1, alias is HMG1 and Amphoterin) is a conserved protein that is widely expressed in almost all types of cells from embryo to adulthood [1,2]
We found that the HMGB1 KO had dramatically upregulated apoptosis in the dorsal neopallial cortex (NPC) between the ventricular zone (VZ) and the marginal layer (MAR) at E12 (Figure 2G)
We previously reported that HMGB1 knockdown in zebrafish embryo causes defective forebrain development due to highly increased Wnt/β-catenin expression [14]
Summary
The High Mobility Group Box 1 protein (HMGB1, alias is HMG1 and Amphoterin) is a conserved protein that is widely expressed in almost all types of cells from embryo to adulthood [1,2]. HMGB1 is the main parental member of the HMG protein family involved in intracellular regulation, but it has extracellular regulatory functions that are related to development, disease, and inflammation. HMGB1 secreted from neurons and from non-neuronal cells [5,6], mainly signals through the RAGE (Receptor for Advanced Glycation End products) receptor [7,8], and it plays an essential role in neurite outgrowth and neuronal migration in the developing nervous system [9]. HMGB1 has been described as an alarmin or damage-associated molecular pattern (DAMP) molecule as for the central role of HMGB1 in inflammation and a relevant molecule in immune responses against tumor formation [13]
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