Loss of cell polarity causes severe brain dysplasia in <i>Lgl1</i> knockout mice

Klezovitch, Olga; Fernandez, Tania E.; Tapscott, Stephen J.; Vasioukhin, Valeri

doi:10.1101/gad.1178004

Cited by 322 publications

(349 citation statements)

References 49 publications

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“…Although it is possible that NMHC II-B serves as a downstream target of aPKC in regulating cell adhesion in the spinal canal, there are other putative targets in the neuronal adherens junction as well, such as PAR3 and Lgl1 (Yamanaka et al, 2003;Klezovitch et al, 2004;Suzuki and Ohno, 2006;Vasioukhin, 2006). In contrast, Even-Faitelson and Ravid (2006) have reported that phosphorylation of the NMHC II-B in the nonhelical tail by an aPKC results in cortical localization of both NM II-B and aPKC in a prostate cancer cell line.…”

Section: Cell-cell Adhesion Of the Neuroepithelial Cells Requires Nonmentioning

confidence: 97%

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

Bao

Adelstein

2007

MBoC

103

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Ablation of nonmuscle myosin (NM) II-B in mice during embryonic development leads to marked enlargement of the cerebral ventricles and destruction of brain tissue, due to hydrocephalus. We have identified a transient mesh-like structure present at the apical border of cells lining the spinal canal of mice during development. This structure, which only contains the II-B isoform of NM, also contains ␤-catenin and N-cadherin, consistent with a role in cell adhesion. Ablation of NM II-B or replacement of NM II-B with decreased amounts of a mutant (R709C), motor-impaired NM II-B in mice results in collapse of the mesh-like structure and loss of cell adhesion. This permits the underlying neuroepithelial cells to invade the spinal canal and obstruct cerebral spinal fluid flow. These defects in the CNS of NM II-B-ablated mice seem to be the cause of hydrocephalus. Interestingly, the mesh-like structure and patency of the spinal canal can be restored by increasing expression of the motor-impaired NM II-B, which also rescues hydrocephalus. However, the mutant isoform cannot completely rescue neuronal cell migration. These studies show that the scaffolding properties of NM II-B play an important role in cell adhesion, thereby preventing hydrocephalus during mouse brain development. INTRODUCTIONCongenital hydrocephalus affects one to three humans per 1000 live births. The results of this abnormality can be devastating in that severe, untreated hydrocephalus can destroy brain tissue and thereby lead to mental retardation. Hydrocephalus occurs when there is an increase in pressure in the ventricular chambers due to a blockage in the circulation of cerebral spinal fluid (CSF) or when there is an increase in production or decrease in the absorption of the CSF. The defect may be accompanied by an obstructed aqueduct of Sylvius, the narrow channel connecting the third and fourth brain ventricles (noncommunicating hydrocephalus), or by a normal aqueduct (communicating hydrocephalus). The pathogenesis of most cases of communicating hydrocephalus is largely unknown (for reviews, see Perez-Figares et al., 2001;Crews et al., 2004).Nonmuscle myosin (NM) II, one of the major cytoskeletal motor proteins, plays an important role in cell migration (Svitkina et al., 1997;Ma et al., 2004;Even-Ram et al., 2007;Vicente-Manzanares et al., 2007), cell-cell adhesion Shewan et al., 2005;Giannone et al., 2007), and cell division (De Lozanne and Spudich, 1987;Takeda et al., 2003;Bao et al., 2005). The molecular structure of NM II is a hexamer consisting of a pair of myosin heavy chains (200 kDa) and two pairs of light chains (20 and 17 kDa). In mammals, three isoforms of the nonmuscle myosin heavy chain (NMHC) have been identified, NMHC II-A, II-B, and II-C, encoded by three different genes, Myh 9, Myh 10, and Myh 14 in humans. The NMHCs share a 60 -80% identity in amino acids, but they show significant differences in their motor activities (Golomb et al., 2004;Kim et al., 2005). In general, all three isoforms are ubiquitously expressed in vertebrat...

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Section: Cell-cell Adhesion Of the Neuroepithelial Cells Requires Nonmentioning

confidence: 97%

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

Bao

Adelstein

2007

MBoC

103

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“…In this mouse, the apical delivery of some proteins, including N-cadherin and aPKC, is impaired resulting in a premature depletion of the stem/precursor pool within the VZ and a consequent reduction of cortical thickness. In addition, disruption of cell polarity and associated loss of AJs in Lgl1 knockout mice result in the appearance of rosettes of mislocalized proliferating stem/precursor cells in areas normally occupied by more differentiated cells (Klezovitch et al, 2004). Such rosettes are also seen in a Kap3 knock-out mouse (Kap3 being part of the Kif3 molecular motor complex), where the delivery of N-cadherin protein at the plasma membrane is impaired (Teng et al, 2005).…”

Section: Similarities and Differences Between Adult And Fetal Neural mentioning

confidence: 99%

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

Lathia

Rao

Mattson

et al. 2007

Developmental Dynamics

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A better understanding of the signals regulating embryonic neural stem cells is clearly an important goal. However, many studies on neural stem cell biology are conducted on the slowly-dividing cells found in the adult CNS, where specialized microenvironments or niches maintain the stem cells throughout life. By contrast, the embryonic VZ is a transient structure that does not fulfill the criteria conventionally used to define niches. In this review we will examine whether, despite these differences, the signals found in other adult stem cell niches are present in the VZ. Using the similarities and differences we observe, we will reconsider whether the location of embryonic stem cell populations such as the VZ can be thought of as niches. Finally, we will ask how these lessons from the niche inform our understanding of neurodevelopmental diseases and cancers of the CNS. Developmental Dynamics 236:3267-3282, 2007.

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“…The adenomatous polyposis coli (APC) gene is required for the asymmetric division of Drosophila spermatogonial stem cells and it is also a critical tumour suppressor in human colon cancer [112][113][114] . A human homologue of the Drosophila gene LgL is HUGL1, which controls cell polarity and is commonly inactivated in cancer in humans and in mice [115][116][117] . Last, inactivation of Numb may in turn activate the Notch signalling pathway, commonly observed in human solid and hematopoietic tumors 118,119 .…”

Section: Asymmetric Division Of Stem Cells and Cancermentioning

confidence: 99%

Somatic stem cells and the origin of cancer

2006

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647Most human cancers derive from a single cell targeted by genetic and epigenetic alterations that initiate malignant transformation. Progressively, these early cancer cells give rise to different generations of daughter cells that accumulate additional mutations, acting in concert to drive the full neoplastic phenotype 1,2 . As we have currently deciphered many of the gene pathways disrupted in cancer, our knowledge about the nature of the normal cells susceptible to transformation upon mutation has remained more elusive. Adult stem cells are those that show long-term replicative potential, together with the capacities of self-renewal and multi-lineage differentiation. These stem cell properties are tightly regulated in normal development, yet their alteration may be a critical issue for tumorigenesis. This concept has arisen from the striking degree of similarity noted between somatic stem cells and cancer cells, including the fundamental abilities to self-renew and differentiate. Given these shared attributes, it has been proposed that cancers are caused by transforming mutations occurring in tissue-specific stem cells 3-9 . This hypothesis has been functionally supported by the observation that among all cancer cells within a particular tumor, only a minute cell fraction has the exclusive potential to regenerate the entire tumor cell population 3,10-13 ; these cells with stem-like properties have been termed cancer stem cells. Cancer stem cells can originate from mutation in normal somatic stem cells that deregulate their physiological programs. Alternatively, mutations may target more committed progenitor cells or even mature cells, which become reprogrammed to acquire stem-like functions 14,15 In any case, mutated genes should promote expansion of stem/progenitor cells, thus increasing their predisposition to cancer development by expanding self-renewal and pluripotency over their normal tendency towards relative quiescency and proper differentiation.

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Loss of cell polarity causes severe brain dysplasia in Lgl1 knockout mice

Cited by 322 publications

References 49 publications

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

Loss of Cell Adhesion Causes Hydrocephalus in Nonmuscle Myosin II-B–ablated and Mutated Mice

The microenvironment of the embryonic neural stem cell: Lessons from adult niches?

Somatic stem cells and the origin of cancer

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