The axon guidance defect of the telencephalic commissures of the JSAP1-deficient brain was partially rescued by the transgenic expression of JIP1

Abstract

The JNK interacting protein, JSAP1, has been identified as a scaffold protein for mitogen-activated protein kinase (MAPK) signaling pathways and as a linker protein for the cargo transport along the axons. To investigate the physiological function of JSAP1 in vivo, we generated mice lacking JSAP1. The JSAP1 null mutation produced various developmental deficits in the brain, including an axon guidance defect of the corpus callosum, in which phospho-FAK and phospho-JNK were distributed at reduced levels. The axon guidance defect of the corpus callosum in the jsap1-/- brain was correlated with the misplacement of glial sling cells, which reverted to their normal position after the transgenic expression of JNK interacting protein 1(JIP1). The transgenic JIP1 partially rescued the axon guidance defect of the corpus callosum and the anterior commissure of the jsap1-/- brain. The JSAP1 null mutation impaired the normal distribution of the Ca+2 regulating protein, calretinin, but not the synaptic vesicle marker, SNAP-25, along the axons of the thalamocortical tract. These results suggest that JSAP1 is required for the axon guidance of the telencephalic commissures and the distribution of cellular protein(s) along axons in vivo, and that the signaling network organized commonly by JIP1 and JSAP1 regulates the axon guidance in the developing brain.

Scaffold proteins of MAP-kinase modules

“…As FAK-activation is required for cell motility, JSAP1-medaited enhanced JNK activation somehow regulates the autophosphorylation as well as kinase activity of FAK, and as JSAP1 associates with microtubules through its interaction with kinesin light chain, it appears that JSAP1 plays a critical role in cell Scaffold proteins of MAP-kinase modules DN Dhanasekaran et al motility. The findings that JSAP1-deficient mice show several abnormalities in brain development including axon guidance defects of the corpus callosum (Kelkar et al, 2003;Ha et al, 2005), and JSAP1-null embryonic stem cells are deficient in the formation of lamellipodial protrusions (Takino et al, 2005), attests to the critical role played by the JSAP1 scaffold in cell motility in organismal development and homeostasis. Furthermore, the observation that the increased expression of JSAP1 and associated activation of JNK and FAK can be associated with advanced malignancy of brain tumors identifies a role for JSAP1 in the pathophysiology of malignant cancers (Takino et al, 2005).…”

Role of mitogen-activated protein kinase kinase 4 in cancer

“…A number of scaffold proteins interact with MKK4 and promote JNK activation including JNK-interacting protein-3 (JIP3) and JIP4 isoforms, plenty of SH3s (POSH), and barrestin-2 (McDonald et al, 2000;Xu et al, 2003b;Whitmarsh, 2006). JIP3 and POSH play important roles in brain development, neuronal trafficking and apoptosis Xu et al, 2003a, b;Ha et al, 2005;Kim et al, 2005), although how these functions relate to their MKK4-JNK scaffolding role is not fully understood. Similarly, the physiological role of the barrestin-2 complex with the JNK pathway is unclear (McDonald et al, 2000).…”

JSAP1/JIP3 and JLP regulate kinesin-1-dependent axonal transport to prevent neuronal degeneration

“…17 Ablating JSAP1 in mice causes various developmental defects in the architecture of the brain, including a lack of telencephalic commissures, whereas no obvious abnormal accumulation of vesicles is observed in the axons. [18][19][20] JLP-null mice are viable and grow normally. 21 On the other hand, JIP1 and JSAP1 were recently shown to be important for the anterograde axonal transport of plasmalemmal precursor vesicles and TrkB, respectively, in rat neurons.…”