Early Forebrain Wiring: Genetic Dissection Using Conditional
            <i>Celsr3</i>
            Mutant Mice

Zhou, Libing; Bar, Isabelle; Achouri, Younès; Campbell, Kenneth; Backer, Olivier De; Hebert, Jean J.M.; Jones, Kevin R.; Kessaris, Nicoletta; Rouvroit, Catherine Lambert de; O’Leary, Dennis D.M.; Richardson, William; Goffinet, André M.; Tissir, Fadel

doi:10.1126/science.1155244

Cited by 161 publications

(202 citation statements)

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“…Ceslr3 conditional knockout mice, we found that Ceslr3 is required in both projecting axons and guidepost cells for axonal pathfinding [44][45][46] . When Celsr3 is removed from the guidepost cells of the basal forebrain using Dlx5/6-Cre, This mimics the flamingo function in regulating tissue polarity as suggested.…”

Section: Two Mouse Mutants Of Celsr1 Have Been Identified Inmentioning

confidence: 81%

Planar cell polarity genes, Celsr1-3, in neural development

2012

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flamingo is among the 'core' planar cell-polarity genes, protein of which belongs to a unique cadherin subfamily.In contrast to the classic cadherins, composed of several extracellular cadherin repeats, one transmembrane domain and one cytoplasmic segment linked to catenin binding, Drosophila Flamingo has seven transmembrane segments and a cytoplasmic tail with no catenin-binding sequence. In Drosophila, Flamingo has pleotropic roles in controlling epithelial polarity and neuronal morphogenesis. Three mammalian orthologs of flamingo, Celsr1-3, are widely expressed in the nervous system. Recent work has shown that Celsr1-3 play important roles in neural development, such as in axon guidance, neuronal migration, and cilium polarity. Celsr1-3 single-gene knockout mice exhibit different phenotypes, but there are cooperative interactions among these genes.

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Section: Two Mouse Mutants Of Celsr1 Have Been Identified Inmentioning

confidence: 81%

Planar cell polarity genes, Celsr1-3, in neural development

2012

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“…We described previously conditional and constitutive Celsr3 mutant mice 23 . The mutant Celsr2 allele was generated by insertion of a targeting vector containing an internal ribosomal entry site (IRES) and the LacZ gene, into exon 23 of the Celsr2 gene, preserving the endogenous splice acceptor ( Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Constitutive Celsr3 mutant mice die at P0 19 . Therefore, we produced Celsr3|Emx1 mice, in which Celsr3 is inactivated in dorsal telencephalon, including the ependymal layer in the roof of lateral ventricles 23 . In these mice, referred to as "Celsr3", cilia were indistinguishable from that in WT cells (Compare Fig.…”

Section: Celsr2 and 3 Have Redundant Functions In Ciliogenesismentioning

confidence: 99%

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Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus

et al. 2010

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Cilia are organelles that protrude from the apical surface of most eukaryotic cells. According to their structure and motility, they are classified into three groups 1 . Primary monocilia, present in most cells, lack a central pair of microtubules (9+0 structure), and play several roles in mechanosensation and cell signaling. Nodal cilia have a 9+0 structure but, unlike primary cilia, they move and generate an asymmetric distribution of morphogenetic cues in the node, thereby contributing to laterality 2 . The third group is composed of motile 9+2 cilia that cover epithelial cells lining airways, reproductive tracts, and cerebral ventricles. Motile cilia play crucial functions in clearing mucus and debris in the airways and may assist the transit of sperm and eggs in genital tracts [3][4] . In the early postnatal mammalian brain, neuroepithelial cells that line the cerebral ventricles leave the cell cycle and differentiate into a monolayer of ependymal cells. At the end of maturation, the apical surface of ependymal cells bears dozens of cilia that beat in coordinate manner to facilitate the circulation of the cerebrospinal fluid (CSF), from sites of production in choroid plexuses to sites of absorption in subarachnoid spaces. In mice, mutations in genes involved in the assembly or structure of ependymal cilia, such as Mdnah5 5 , Ift88 (also known as Tg737 or Polaris) 6 , and Hy3 7-8 affect cilia genesis, CSF dynamics, and result in hydrocephalus. Thus far, however, little is known about the genetic factors that govern ependymal cilia polarization and the relationship between the polarity and the development and function of these organelles.Planar cell polarity (PCP), also known as tissue polarity, controls the polarization of epithelial cells in a plane perpendicular to their apicobasal axis. It was initially described in Drosophila, where it affects the stereotypic arrangement of cuticular hairs, sensory bristles, and Supplementary Fig. 1a, b). RT-PCR and (Supplementary Fig. 1c).Using the knocked-in beta-galactosidase reporter, we monitored the expression of Celsr2 in heterozygous mice. Consistent with published data [24][25][26] , Celsr2 expression was detected in all brain areas, from E11.5 to P5 (Fig. 1a-h). Celsr2 mutant mice develop progressive hydrocephalusCelsr2 mutant mice were viable and fertile, except for some females that had vaginal atresia. At birth, their brain did not display any flagrant morphological abnormality, suggesting that Celsr2 is not critical for cerebral embryonic development. However, a progressive ventricular dilation appeared between P5 and P10 with variable severity between animals, and became evident at P21 (Fig. 2a,b).The lateral ventricles were enlarged, and the septum had an abnormal triangular shape, due to 6 6 reduction of the dorsal part of the lateral septum. We did not observe any stenosis or constriction at the level of the foramen of Monro or of the aqueduct. The subcommissural organ (SCO), a structure thought to play a role in non-communicating hydrocephalus, was...

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“…Loss of DN-Cadherin in fly embryos induces defasciculation and misorientation of axons (Iwai et al 1997). In null mouse mutants of Celsr3, an atypical cadherin/Drosophila flamingo homologue, the extension of subcortical projections to and within the cortex are impaired and cortex-specific inactivation impairs projections to the cortex (Zhou et al 2008). In the L1 null mouse thalamocortical axons are hyper-fasciculated and make guidance errors (Wiencken-Barger et al 2004).…”

Section: Adhesive Cuesmentioning

confidence: 99%

Cellular Strategies of Axonal Pathfinding

Raper

Mason

2010

Cold Spring Harbor Perspectives in Biology

157

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Axons follow highly stereotyped and reproducible trajectories to their targets. In this review we address the properties of the first pioneer neurons to grow in the developing nervous system and what has been learned over the past several decades about the extracellular and cell surface substrata on which axons grow. We then discuss the types of guidance cues and their receptors that influence axon extension, what determines where cues are expressed, and how axons respond to the cues they encounter in their environment.T his article provides an overview of how growth cones respond to the cellular substrata and molecular cues they encounter as they extend through the developing nervous system. It elaborates on the primer by Kolodkin and TessierLavigne (2010) and touches on many of the topics covered in greater detail in the articles that follow. The first sections describe how axons extend in a directed manner, the substrata on which they grow, interactions between pioneer and follower axons, and growth cone behaviors in emerging tracts and at decision points. The subsequent sections discuss examples of specific cues, their distributions, how their distributions are determined, and how growth cones integrate multiple cues during pathfinding. AXONS EXTEND IN VIVO IN A DIRECTED MANNERThe first person to visualize the growing tips of axons, Ramon y Cajal, recognized that axons for the most part grow very efficiently towards their ultimate targets. He was a strong advocate for axons finding their way in response to chemotactic cues:"If one admits that neuroblasts are endowed with chemotactic properties, then one might also imagine that they are capable of ameboid movements, initiated by factors secreted from epithelial, neural, or mesodermal elements. As a result, their processes may be oriented in the direction of chemical gradients, and thus guided to the secreting cells" (Ramon y Cajal 1892; trans. English, 1995).This surprisingly modern outlook emphasizing directed guidance was temporarily derailed by the views of Weiss during the 1920s and 1930s. He first argued that functional specificity did not arise as a consequence of specific axonal connections (Weiss 1936), and later argued that nonspecific mechanical guidance cues play a predominant role in guiding axons and organizing them into nerves and tracts

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Early Forebrain Wiring: Genetic Dissection Using Conditional Celsr3 Mutant Mice

Cited by 161 publications

References 25 publications

Planar cell polarity genes, Celsr1-3, in neural development

Planar cell polarity genes, Celsr1-3, in neural development

Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus

Cellular Strategies of Axonal Pathfinding

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