Disease relevance of Pafah1b1

• Ablation of the LIS1-interacting protein Nde1 (formerly mNudE) in mouse produces a small brain (microcephaly), with the most dramatic reduction affecting the cerebral cortex [1].
• Inactivation of a testis-specific Lis1 transcript in mice prevents spermatid differentiation and causes male infertility [2].
• Retraction of radial glial endfeet, midline fusion of brain hemispheres, and gliosis also occurred, similar to type II cobblestone lissencephaly as seen in congenital muscular dystrophy [3].

Psychiatry related information on Pafah1b1

• Type I lissencephaly is a central nervous system (CNS) malformation characterized by mental retardation and epilepsy [4].

High impact information on Pafah1b1

• Pafah1b1(+/-) mice have hippocampal layering defects, whereas homozygous mutants are embryonic lethal [5].
• The phenotypes observed are distinct from those of other mouse mutants with neuronal migration defects, suggesting that Pafah1b1 participates in a novel pathway for neuronal migration [6].
• Mice with further reduction of Pafah1b1 activity display more severe brain disorganization as well as cerebellar defects [6].
• Our results demonstrate an essential, dosage-sensitive neuronal-specific role for Pafah1b1 in neuronal migration throughout the brain, and an essential role in early embryonic development [6].
• Recently, we and others reported that the doublecortin gene is responsible for X-linked lissencephaly and subcortical laminar heterotopia [7].

Biological context of Pafah1b1

• Our data provide evidence for unique roles of the PAFAH1B complex and, particularly, the lissencephaly protein Lis1 in spermatogenesis [8].
• Besides the brain, transcripts for Lis1, alpha1, and alpha2 are localized to meiotic and early haploid germ cells [8].
• Characterization and chromosomal mapping of two pseudogenes of the mouse Pafaha/Lis1 gene: retrointegration hotspots in the mouse genome [9].
• We propose a model in which Lis1 stimulates the activity of a subset of motors, which could be particularly important during neuronal migration and long-distance axonal transport [10].
• A role for cytoplasmic dynein and LIS1 in directed cell movement [11].

Anatomical context of Pafah1b1

• Rescue of these defects in mouse embryonic fibroblasts and granule cells by overexpressing LIS1, NDEL1, or NDE1 suggest that NDEL1, LIS1, and NDE1 act in a common pathway to regulate dynein but each has distinct roles in the regulation of microtubule organization and neuronal migration [12].
• Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons [13].
• Lis1 is necessary for normal non-radial migration of inhibitory interneurons [4].
• We have generated a mouse mutant (LIS1GT/GT) by gene trap integration leading to selective disruption of a Lis1 splicing variant in testis [2].
• These results provide evidence for an essential and hitherto uncharacterized role of the Lis1 protein in spermatogenesis, particularly in the differentiation of spermatids into spermatozoa [2].

Associations of Pafah1b1 with chemical compounds

• The deletion resulted in a shorter protein (sLIS1) that initiates from the second methionine, a unique situation because most LIS1 mutations result in a null allele [14].
• With the lithium diiodosalicylate (LIS1) extraction-phenol partition method, we have isolated a sialoglycoprotein fraction from DBA/2 mouse erythrocyte ghosts [15].

Regulatory relationships of Pafah1b1

• These data indicate a previously unrecognized role for Lis1 protein in neuronal motility by promoting actin polymerization through the regulation of Rho GTPase activity [13].

Other interactions of Pafah1b1

• Our results indicate that, in hippocampal neurons, MAP1B and LIS1 co-localize, associate and interact with each another [16].
• Regulation of cytoplasmic dynein ATPase by Lis1 [10].
• We now find that dynein and its regulators dynactin and LIS1 localize to the leading cell cortex during this process [11].
• We have examined the effect of disorganisation of the mitral cell soma layer in mutant mice heterozygous for the beta-subunit of platelet activating factor acetylhydrolase (Lis1(-/+)) on the targeting of primary olfactory axons [17].
• Integrin-linked kinase deletion from mouse cortex results in cortical lamination defects resembling cobblestone lissencephaly [18].

Analytical, diagnostic and therapeutic context of Pafah1b1

• Northern blot analysis revealed that the various Pafaha/Lis1 mRNAs are differentially expressed in mouse tissues [19].
• Combined Western and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analyses showed that LIS1 expression from the blastocyst stage required new transcription from the embryonic genome [20].
• We have now mapped the mouse homolog of LIS-1 to mouse chromosome 11B3 by using fluorescence in situ hybridization to metaphase chromosomes [21].

References