Aphakia, a New Mutation in the Mouse

Varnum, Don S.; Stevens, Leroy C.

doi:10.1093/oxfordjournals.jhered.a107667

Cited by 102 publications

(60 citation statements)

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“…Aphakia is an autosomal recessive disorder in which adult homozygotes (ak/ak) have closed eyelids resulting from aberrant embryonic lens development (19). The defect produces a malformed lens vesicle that fails to develop beyond embryonic day (E) 11.5 and by E14.5 involutes into a clump of crystallin-negative cells (20).…”

Section: Resultsmentioning

confidence: 99%

Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo.

Liégeois

Horner

DePinho

1996

Proc. Natl. Acad. Sci. U.S.A.

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A genetic approach has been established that combines the advantages of blastocyst complementation with the experimental attributes of the developing lens for the functional analysis of genes governing cellular proliferation, terminal differentiation, and apoptosis. This lens complementation system (LCS) makes use of a mutant mouse strain, aphakia (ak), homozygotes of which fail to develop an ocular lens. We demonstrate that microinjection of wild-type embryonic stem (ES) cells into ak/ak blastocysts produces chimeras with normal ES-cell-derived lenses and that microinjection of Rb-/-ES cells generates an aberrant lens phenotype identical to that obtained through conventional gene targeting methodology. Our determination that a cell autonomous defect underlies the aphakia condition assures that lenses generated through LCS are necessarily ES-cell-derived. LCS provides for the rapid phenotypic analysis of loss-of-function mutations, circumvents the need for germ-line transmission of null alleles, and, most significantly, facilitates the study of essential genes whose inactivation is associated with early lethal phenotypes.The capacity to manipulate the genetic composition of the mouse has allowed for significant advances in the study of developmental and cancer biology. Much of this progress is the result of methods that permit the precise structural alteration of genes through homologous recombination in embryonic stem (ES) cells followed by germ-line transmission of these targeted alleles through chimera formation (1). Successful implementation of gene targeting requires maintenance of ES-cell pluripotency to passage the mutant allele through the germ line. A potential impediment to the analysis of loss-offunction mutations generated through the classical knockout approach is attendant embryonic lethality. This outcome is particularly problematic in cancer-relevant models wherein early lethality contracts the time available for the emergence of additional genetic lesions that cooperate to bring about a fully transformed state. Procedural modifications developed to circumvent some of these obstacles include the generation of chimeras from homozygous null ES cells (2) and the use of a modified Cre-LoxP approach for the production of a celltype-specific nullizygous condition (3). However, the former approach requires a detailed in situ .assessment of whether tissues of the chimera are ES-or host blastocyst-derived, and the latter can be complicated by mosaicism caused by inefficient Cre-mediated deletion (A. Nagy, personal communication).To overcome these problems, Chen et al. (4) developed a method for evaluating gene function in the immune system that makes use of host blastocysts derived from RAG-2-deficient mice, which are incapable of variable-diversity-joining (VDJ) recombination and thus lack mature B and T lymphocytes. Injection of normal or genetically modified ES cells into theseThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be here...

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Section: Resultsmentioning

confidence: 99%

Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo.

Liégeois

Horner

DePinho

1996

Proc. Natl. Acad. Sci. U.S.A.

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“…There are several ocular phenotypes that involve lens degeneration including aphakia [62-64], dysgenetic lens [65-67], lens aplasia [68,69] in mice. Genes responsible for the aphakia and dysgenetic lens phenotypes have been identified as transcription factors, Pitx3 and Foxe3 ; both genes were also shown to be involved in human ocular disorders involving abnormal lens, iris and corneal development [54,55] and zebrafish pitx3 -morphants displayed lens degeneration similar to mammals [70].…”

Section: Discussionmentioning

confidence: 99%

laminin alpha 1gene is essential for normal lens development in zebrafish

et al. 2006

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BackgroundLaminins represent major components of basement membranes and play various roles in embryonic and adult tissues. The functional laminin molecule consists of three chains, alpha, beta and gamma, encoded by separate genes. There are twelve different laminin genes identified in mammals to date that are highly homologous in their sequence but different in their tissue distribution. The laminin alpha -1 gene was shown to have the most restricted expression pattern with strong expression in ocular structures, particularly in the developing and mature lens.ResultsWe identified the zebrafish lama1 gene encoding a 3075-amino acid protein (lama1) that possesses strong identity with the human LAMA1. Zebrafish lama1 transcripts were detected at all stages of embryo development with the highest levels of expression in the developing lens, somites, nervous and urogenital systems. Translation of the lama1 gene was inhibited using two non-overlapping morpholino oligomers that were complementary to sequences surrounding translation initiation. Morphant embryos exhibited an arrest in lens development and abnormalities in the body axis length and curvature.ConclusionThese results underline the importance of the laminin alpha 1 for normal ocular development and provide a basis for further analysis of its developmental roles.

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“…The in vivo role of Pitx3 in the mesDA system was analyzed by using the ak mouse (17). A spontaneous mutation of the Pitx3 locus in the ak mouse resulted in a null allele lacking putative regulator elements and promoter sequences (18,19).…”

Section: Th Ir In the Adult Ak Mousementioning

confidence: 99%

Pitx3 is required for development of substantia nigra dopaminergic neurons

Nunes

Tovmasian

Silva

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

350

271

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Dopaminergic (DA) neurons of substantia nigra in the midbrain control voluntary movement, and their degeneration is the cause of Parkinson's disease. The complete set of genes required to specifically determine the development of midbrain DA subgroups is not known yet. We report here that mice lacking the bicoidrelated homeoprotein Pitx3 fail to develop DA neurons of the substantia nigra. Other mesencephalic DA neurons of the ventral tegmental area and retrorubral field are unaltered in their dopamine expression and histological organization. These data suggest that Pitx3-dependent gene expression is specifically required for the differentiation of DA progenitors within the mesencephalic DA system. M idbrain dopaminergic (DA) cells contribute to the control of voluntary movement, cognition, and emotional behavior. Degeneration of these cells results in Parkinson's disease, and aberrant dopamine neurotransmitter signaling is implicated in schizophrenia and addictive behavioral disorders (1-3). Within the midbrain there are three subgroups of DA neurons, the ventral tegmental area (VTA͞A10), substantia nigra (SN͞ A9), and retrorubral field (RRF͞A8), that together constitute the mesencephalic (mes) system (4). Those DA cells in the SN that innervate the striatum preferentially degenerate in Parkinson's disease, whereas other DA subgroups regulate emotional and reward behaviors.Transcription factors regulate the differentiation of midbrain DA neuron precursors. Two transcription factors have been shown to contribute to different aspects of mesDA neuronal differentiation. One of these, the orphan nuclear hormone receptor Nurr1, is required for maturation of mesDA neuron precursors. Mice harboring null alleles of Nurr1 do not express tyrosine hydroxylase (TH), which catalyzes the initial step of dopamine neurotransmitter biosynthesis (5-11). The other factor, LIM homeodomain transcription factor Lmx1b, contributes partially to the specification of mesDA neuronal progenitors beginning on embryonic day 12.5 in the mouse but is not essential for TH gene expression (12).A third transcription factor, the bicoid-related homeodomain-containing transcription factor Pitx3, which is also known as Ptx3, has been implicated in the development of DA neurons. Pitx3 gene expression is restricted to the developing eye and DA progenitor cells from embryonic day 11 throughout adult life in mice (13,14). In the brain, Pitx3 mRNA localizes specifically to the SN and VTA (14). A reduction in Pitx3 mRNA levels is observed in the ventral midbrain of Lmx1b knockout mice, 6-hydroxydopamine-lesioned rats, and Parkinson's patients (8,11,12,14). Yet, Pitx3 expression is maintained in the ventral midbrain of Nurr1 null mutant embryos (12). These data have been interpreted to suggest that Pitx3 contributes to the combinatorial code defined by multiple transcription factors that establish specification and differentiation of midbrain DA progenitors (12). Here we report that Pitx3 is essential for the development of neurons specific to the SN. The D...

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Aphakia, a New Mutation in the Mouse

Cited by 102 publications

References 0 publications

Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo.

Lens complementation system for the genetic analysis of growth, differentiation, and apoptosis in vivo.

laminin alpha 1gene is essential for normal lens development in zebrafish

Pitx3 is required for development of substantia nigra dopaminergic neurons

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