title: Mutation of the BiP/GRP78 gene causes axon outgrowth and fasciculation defects in the thalamocortical connections of the mammalian forebrain.
abstract: Proper development of axonal connections is essential for brain function. A forward genetic screen for mice with defects in thalamocortical development previously isolated a mutant called baffled. Here we describe the axonal defects of baffled in further detail and identify a point mutation in the Hspa5 gene, encoding the endoplasmic reticulum chaperone BiP/GRP78. This hypomorphic mutation of BiP disrupts proper development of the thalamocortical axon projection and other forebrain axon tracts, as well as cortical lamination. In baffled mutant brains, a reduced number of thalamic axons innervate the cortex by the time of birth. Thalamocortical and corticothalamic axons are delayed, overfasciculated, and disorganized along their pathway through the ventral telencephalon. Furthermore, dissociated mutant neurons show reduced axon extension in vitro. Together, these findings demonstrate a sensitive requirement for the endoplasmic reticulum chaperone BiP/GRP78 during axon outgrowth and pathfinding in the developing mammalian brain.
authors: Department of Cell Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors: Carlita B
authors: CB
authors: Favero
authors: Rasha N
authors: RN
authors: Henshaw
authors: Cynthia M
authors: CM
authors: Grimsley-Myers
authors: Ayushma
authors: A
authors: Shrestha
authors: David R
authors: DR
authors: Beier
authors: Noelle D
authors: ND
authors: Dwyer
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000002:abnormalities* / Q000166:cytology / Q000502:physiology; D000091342:Endoplasmic Reticulum Chaperone BiP; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D005820:Genetic Testing; D005865:Gestational Age; D006360:Heat-Shock Proteins / Q000235:genetics*; D008297:Male; D008322:Mammals; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D009434:Neural Pathways / Q000002:abnormalities / Q000166:cytology / Q000502:physiology; D011247:Pregnancy; D016548:Prosencephalon / Q000002:abnormalities / Q000166:cytology / Q000502:physiology; D013788:Thalamus / Q000002:abnormalities* / Q000166:cytology / Q000502:physiology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse