Farnesylation of lamin B1 is important for retention of nuclear chromatin during neuronal migration

Abstract

The role of protein farnesylation in lamin A biogenesis and the pathogenesis of progeria has been studied in considerable detail, but the importance of farnesylation for the B-type lamins, lamin B1 and lamin B2, has received little attention. Lamins B1 and B2 are expressed in nearly every cell type from the earliest stages of development, and they have been implicated in a variety of functions within the cell nucleus. To assess the importance of protein farnesylation for B-type lamins, we created knock-in mice expressing nonfarnesylated versions of lamin B1 and lamin B2. Mice expressing nonfarnesylated lamin B2 developed normally and were free of disease. In contrast, mice expressing nonfarnesylated lamin B1 died soon after birth, with severe neurodevelopmental defects and striking nuclear abnormalities in neurons. The nuclear lamina in migrating neurons was pulled away from the chromatin so that the chromatin was left "naked" (free from the nuclear lamina). Thus, farnesylation of lamin B1-but not lamin B2-is crucial for brain development and for retaining chromatin within the bounds of the nuclear lamina during neuronal migration.genetically modified mouse models T he nuclear lamina is an intermediate filament meshwork that lies beneath the inner nuclear membrane. This lamina provides structural support for the nucleus and also interacts with nuclear proteins and chromatin, thereby affecting many functions within the cell nucleus (1, 2). In mammals, the main protein components of the nuclear lamina are lamins A and C (A-type lamins) and lamins B1 and B2 (B-type lamins).Both B-type lamins and prelamin A (the precursor of lamin A) terminate with a CaaX motif, which triggers three posttranslational modifications (3-5): farnesylation of the carboxyl-terminal cysteine (the "C" in the CaaX motif) (6), endoproteolytic cleavage of the last three amino acids (the -aaX) (7,8), and carboxyl methylation of the newly exposed farnesylcysteine (9, 10). Prelamin A undergoes a second endoproteolytic cleavage event, mediated by zinc metalloproteinase STE24 (ZMPSTE24), which removes 15 additional amino acids from the carboxyl terminus, including the farnesylcysteine methyl ester (11)(12)(13)(14). Lamins B1 and B2 do not undergo the second cleavage step and therefore retain their farnesyl lipid anchor.The discovery that Hutchinson-Gilford progeria syndrome (HGPS) is caused by a LMNA mutation yielding an internally truncated farnesyl-prelamin A (15) has focused interest in the farnesylation of nuclear lamins. This interest has been fueled by the finding that disease phenotypes in mouse models of HGPS could be ameliorated by blocking protein farnesylation with a protein farnesyltransferase inhibitor (FTI) (16)(17)(18)(19). Most recently, children with HGPS seemed to show a positive response to FTI treatment (20).The prospect of using an FTI to treat children with HGPS naturally raises the issue of the importance of protein farnesylation for lamin B1 and lamin B2. The B-type lamins are expressed in all mammalian cells and have been h...

An Absence of Nuclear Lamins in Keratinocytes Leads to Ichthyosis, Defective Epidermal Barrier Function, and Intrusion of Nuclear Membranes and Endoplasmic Reticulum into the Nuclear Chromatin

“…Three of the nuclear lamins (prelamin A, lamin B1, and lamin B2) are modified by a farnesyl lipid. In the case of lamin B1, this lipid modification is crucial for the migration of neurons in the developing brain (37). For other cell types, for example, keratinocytes, the importance of lamin farnesylation is unclear.…”

“…Prelamin A, lamin B1, and lamin B2 are farnesylated proteins. Cell culture studies have suggested that the farnesylation of nuclear lamins is important for targeting those proteins to the nuclear envelope (14)(15)(16)(17)(18), and an absence of lamin B1 farnesylation causes severe neurodevelopmental abnormalities (37). One…”

The Nuclear Envelope: An Intriguing Focal Point for Neurogenetic Disease

“…In mice, B-type lamins have been shown to be essential for neuronal migration, whereby loss of B-type lamins causes lissencephaly-like defects in cortical development [84][85][86]. This has led to the prediction that whole-exome sequencing on patients with severe neurological diseases will eventually uncover nonsense and missense mutations in LMNB1 and LMNB2 [85].…”

Do lamin B1 and lamin B2 have redundant functions?

“…Second, the importance of protein farnesylation is different for lamin B1 and lamin B2. Jung et al 29 generated knock-in mice that produced nonfarnesylated versions of lamin B1 and lamin B2 (by replacing the cysteine of the CaaX motif with a serine). Knock-in mice expressing nonfarnesylated lamin B2 were healthy, fertile, and free of behavioral abnormalities; neither neuropathology nor nuclear shape abnormalities were detected in the cerebral cortex.…”

“…Dumbbell-shaped nuclei were also found in cultured neurons as they migrated away from neurospheres. Jung et al 29 suggested that dumbbell-shaped nuclei were the consequence of defective anchoring of lamin B1 to the inner nuclear membrane and honeycombing of the nuclear lamina. They proposed that, during nucleokinesis, the lamina was pulled into the leading edge of the cell in a normal fashion, but the nuclear chromatin did not "come along for the ride."…”