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Abstract
Hmgb1 (high mobility group box-1; amphoterin) is highly expressed in brain during early development of vertebrate and nonvertebrate species. However, its role in brain development remains elusive. Here we have cloned the zebrafish Hmgb1 and specifically manipulated Hmgb1 expression using injection of morpholino antisense oligonucleotides or Hmgb1 cRNA. The HMGB1 knockdown morphants produced by injection of three different morpholino oligonucleotides display a characteristic phenotype with smaller size, smaller brain width, and shorter distance between the eyes. Closer examination of the phenotype reveals severe defects in the development of the forebrain that largely lacks catecholaminergic neural networks. The HMGB1 morphant is deficient in survival and proliferation of neural progenitors and displays fewer cell groups expressing the transcription factor Pax6a in the forebrain and aberrant Wnt8 signaling. The mechanism of HMGB1-dependent progenitor survival involves the neuronal transmembrane protein AMIGO (amphoterin-induced gene and orf), the expression of which is regulated by HMGB1 in vivo. Our data demonstrate that HMGB1 is a critical factor for brain development, enabling survival and proliferation of neural progenitors that will form the forebrain structures.
Highlights
IntroductionFoundation. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs
Foundation. □S The on-line version of this article contains supplemental Figs
A high expression level of HMGB1 has been demonstrated in embryonic rat brain compared with the adult brain [6], and mapping studies using in situ hybridization have shown that during organogenesis in zebrafish HMGB1 is essentially a nervous system protein that is abundantly expressed in brain
Summary
Foundation. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. HMGB1 was isolated from developing rat brain using neurite outgrowth in embryonic forebrain neurons as a readout in protein fractionation [6]. These studies provided the initial evidence of HMGB1 as an extracellularly acting protein (6 – 8), which has become the major line of HMGB1 research during the last few years. HMGB1 has been shown to bind to RAGE and to enhance tumor growth and spread [10] Despite these in vitro and in vivo findings, which would be compatible with a developmental role for HMGB1, its possible role in brain development has not been explored. Hmgb is highly expressed in early embryonic brain and might, have a role in the development of ancestral forms of complex brain structures
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