Abstract
Goldberg-Shprintzen syndrome is a poorly understood condition characterized by learning difficulties, facial dysmorphism, microcephaly, and Hirschsprung disease. GOSHS is due to recessive mutations in KIAA1279, which encodes kinesin family member 1 binding protein (KIF1BP, also known as KBP). We examined the effects of inactivation of Kif1bp in mice. Mice lacking Kif1bp died shortly after birth, and exhibited smaller brains, olfactory bulbs and anterior commissures, and defects in the vagal and sympathetic innervation of the gut. Kif1bp was found to interact with Ret to regulate the development of the vagal innervation of the stomach. Although newborn Kif1bp−/− mice had neurons along the entire bowel, the colonization of the gut by neural crest-derived cells was delayed. The data show an essential in vivo role for KIF1BP in axon extension from some neurons, and the reduced size of the olfactory bulb also suggests additional roles for KIF1BP. Our mouse model provides a valuable resource to understand GOSHS.
Highlights
Goldberg-Shprintzen syndrome (GOSHS, OMIM 609460) is a rare human condition characterized by intellectual disability, microcephaly, dysmorphic facial features, peripheral neuropathy as well as Hirschsprung disease in which neurons are absent from the distal bowel[1,2,3,4]
We generated Kif1bp null mice using Crispr/Cas[9]. Both mouse lines generated showed the same phenotype of neonatal death, decreased brain size, including cerebral cortex, smaller and disorganised olfactory bulbs, reduced anterior commissure, delayed enteric neural crest colonisation of the gut and defective vagal and sympathetic innervation of the gut
We did not observe craniofacial abnormalities or HSCR in the mouse model. These latter aspects of the phenotype are similar to kif1bp mutant zebrafish, which displayed reduced axonal growth, but neurons were present along the length of the gut and no craniofacial abnormalities were observed[7]
Summary
Goldberg-Shprintzen syndrome (GOSHS, OMIM 609460) is a rare human condition characterized by intellectual disability, microcephaly, dysmorphic facial features, peripheral neuropathy as well as Hirschsprung disease in which neurons are absent from the distal bowel[1,2,3,4]. Mouse and zebrafish have shown that KIF1BP is expressed in most tissues[5,6,7] (www.brain-map.org/). Despite the widespread expression of KIF1BP5, GOSHS primarily affects the development of neurons and neural crest-derived tissues[4,6]. Studies using cell lines and zebrafish mutants suggest the main role of KIF1BP is to regulate axon extension. Kif1bp mutant zebrafish have neurons along the entire length of the bowel and do not develop a Hirschsprung disease-like phenotype[7]. Study confirms a role for KIF1BP in axon extension from subpopulations of peripheral and CNS neurons in vivo, but the smaller brain and olfactory bulbs we observed in Kif1bp null mutants suggest additional roles for KIF1BP during nervous system development
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