High mobility group box-1 (HMGB1; amphoterin) is required for zebrafish brain development

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 anti-sense oligonucleotides (MOs) or Hmgb1 cRNA. The HMGB1 knockdown morphants produced by injection of three different MOs 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 less cell groups expressing the transcription factor Pax6a in the forebrain and aberrant Wnt8 signalling. 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.