Heat Shock Proteins Regulatory Role in Neurodevelopment

Abstract

Heat shock proteins (Hsps) are a large family of molecular chaperones that are well-known for their roles in protein maturation, re-folding and degradation. While some Hsps are constitutively expressed in certain regions, others are rapidly upregulated in the presence of stressful stimuli. Numerous stressors, including hyperthermia and hypoxia, can induce the expression of Hsps, which, in turn, interact with client proteins and co-chaperones to regulate cell growth and survival. Such interactions must be tightly regulated, especially at critical points during embryonic and postnatal development. Hsps exhibit specific patterns of expression consistent with a spatio-temporally regulated role in neurodevelopment. There is also growing evidence that Hsps may promote or inhibit neurodevelopment through specific pathways regulating cell differentiation, neurite outgrowth, cell migration, or angiogenesis. This review will examine the regulatory role that these individual chaperones may play in neurodevelopment, and will focus specifically on the signaling pathways involved in the maturation of neuronal and glial cells as well as the underlying vascular network.

Keywords: axon guidance; cell migration; heat shock proteins; neurite extension; neurodevelopment; neurovascular unit.

FIGURE 1

Potential intracellular roles of heat shock proteins in development. Intracellular Hsps, such as HspB1 and Hsp90, directly regulate client proteins involved in cell growth and migration (A), and may play an important role in neurodevelopment. HspB1, in particular, may also regulate neurite extension through the upregulation of non-coding RNAs that inhibit RhoA-ROCK signaling (B). Other Hsps, such as Hsp70, have been shown to competitively inhibit Raf-1-BAG-1-mediated cell growth and differentiation (C). This novel role of Hsp70 may be especially important given its ability to be rapidly induced. Abbreviations: PI3K, phosphoinositide 3-kinase; GSK3, glycogen synthase kinase 3; BAG-1, Bcl2-associated anthogene-1; RhoGEF, Ras homolog guanine exchange factor; RhoA, Ras homolog gene family, member A; ROCK, Rho-associated protein kinase.

FIGURE 2

Potential extracellular roles of heat shock proteins in development. Although the exact mechanisms remain unclear, extracellular α-crystallins have been shown to promote axon guidance and neurite extension through inhibition of RhoA-ROCK signaling. Other extracellular Hsps, namely Hsp70 and Hsp90, have been suggested to interact with the Hsp70-Hsp90-organizing protein (HOP) and promote neuronal and glial migration through receptors such as toll-like receptor 4 (TLR4). In contrast, extracellular HspB1 has been shown to inhibit vascular endothelial growth factor (VEGF)-A signaling and angiogenesis by direct inhibition of VEGF-A. Abbreviations: RhoA, Ras homolog gene family, member A; ROCK, Rho-associated protein kinase; PI3K, phosphoinositide 3-kinase; MMP, matrix metalloproteinase; NFκB, nuclear factor κ light chain enhancer of activated B cells.