Progression from mitotic catastrophe to germ cell death in Caenorhabditis elegans lis-1 mutants requires the spindle checkpoint.
Deletion of the lissencephaly disease gene LIS-1 in humans causes an extreme disorganization of the brain associated with significant reduction in cortical neurons. Here we show that deletion or RNA interference (RNAi) of Caenorhabditis elegans lis-1 results in a reduction in germline nuclei and causes a variety of cellular, developmental, and neurological defects throughout development. Our analysis of the germline defects suggests that the reduction in nuclei number stems from dysfunctional mitotic spindles resulting in cell cycle arrest and eventually programmed cell death (apoptosis). Deletion of the spindle checkpoint gene mdf-1 blocks lis-1(lf)-induced cell cycle arrest and germline apoptosis, placing the spindle checkpoint pathway upstream of the programmed cell death pathway. These results suggest that apoptosis may contribute to the cell-sparse pathology of lissencephaly.
Buttner
Edgar A
EA
Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, MA 02138-2020, USA. nbuttner@gmail.com
Gil-Krzewska
Aleksandra J
AJ
Rajpurohit
Anandita K
AK
Hunter
Craig P
CP
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000502:physiology; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000502:physiology; D029742:Caenorhabditis elegans Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology*; D017353:Gene Deletion; D008297:Male; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D008938:Mitosis / Q000235:genetics* / Q000502:physiology; D008969:Molecular Sequence Data; D015398:Signal Transduction / Q000235:genetics; D013094:Spermatozoa / Q000473:pathology*; D008941:Spindle Apparatus / Q000235:genetics* / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; C412839:MDF-1 protein, C elegans; D008869:Microtubule-Associated Proteins; C513193:lis-1 protein, C elegans