A role for the lissencephaly gene LIS1 in mitosis and cytoplasmic dynein function

Abstract

Mutations in the LIS1 gene cause gross histological disorganization of the developing human brain, resulting in a brain surface that is almost smooth. Here we show that LIS1 protein co-immunoprecipitates with cytoplasmic dynein and dynactin, and localizes to the cell cortex and to mitotic kinetochores, which are known sites for binding of cytoplasmic dynein. Overexpression of LIS1 in cultured mammalian cells interferes with mitotic progression and leads to spindle misorientation. Injection of anti-LIS1 antibody interferes with attachment of chromosomes to the metaphase plate, and leads to chromosome loss. We conclude that LIS1 participates in a subset of dynein functions, and may regulate the division of neuronal progenitor cells in the developing brain.

LIS1—no more no less

“…59 Nevertheless, in both mutations homozygous mutant animals exhibit early lethality, probably relating to LIS1 function in mitosis. 26 This study provides insight into how different functional alleles of LIS1 may produce the range of phenotypes observed in humans. Our detailed analysis identified the dorsal telencephalon as the most vulnerable to LIS1 dosage and that formation of the cortical plate, neuronal migration, neuronal morphology, and radial glia morphology are sensitive to LIS1 function.…”

“…25 Dynein, dynactin and LIS1 co-immunoprecipitate and colocalize in tissue culture and in the brain. 26,27 Microtubule-based motor proteins are essential components of the mitotic spindle and are required for segregation of sister chromatids (recently reviewed by Sharp et al 28 ). Indeed, overexpression of LIS1 in cultured mammalian cells interfered with mitotic progression and led to spindle misorientation.…”

“…Indeed, overexpression of LIS1 in cultured mammalian cells interfered with mitotic progression and led to spindle misorientation. 26 Furthermore, injection of anti-LIS1 antibodies disrupted attachment of chromosomes to the metaphase plate and led to chromosome loss. 26 Dynein function is not restricted to mitosis.…”

“…26 Furthermore, injection of anti-LIS1 antibodies disrupted attachment of chromosomes to the metaphase plate and led to chromosome loss. 26 Dynein function is not restricted to mitosis. Dynein's roles in intracellular transport are highly developed in neurons due to their large size, polarization, and ability to communicate at long distances (recently reviewed by Goldstein and Yang 29 ).…”

Novel isoforms of intracellular platelet activating factor acetylhydrolase (PAFAH1b2) in human testis; encoded by alternatively spliced mRNAs

“…This link to cell division bears an interesting parallel to the Beta subunit of Paf-ah-Ib (LIS1) which, in addition to its regulatory role in Paf-ah-Ib, is involved in microtubule associated processes in cell division (24). The association of LIS1 with microtubule associated proteins is reported to be regulated by phosphorylation (25), and a testis specific splice variant as well as polyadenylation variants have been reported for LIS1 mRNA in mice (26).…”