6 research outputs found
Retinitis pigmentosa: Cone photoreceptors starving to death
In retinitis pigmentosa, rod and cone photoreceptors die. Although rods die as a consequence of rod-specific genetic mutations, there is no clear explanation for the progressive loss of cones. A new study in this issue suggests that changes in the insulin/mTOR pathway and cell starvation can partially account for cone death in this disease. © 2009 Nature America, Inc. All rights reserved.Peer Reviewe
Cell cycle control of Notch signaling and the functional regionalization of the neuroepithelium during vertebrate neurogenesis
A critical feature of vertebrate neural precursors is the to-and-fro displacement of their nuclei as cell cycle progresses, thus giving rise to a pseudostratified epithelium. This nuclear behavior, referred to as interkinetic nuclear migration (INM), is translated into the disposition of the cell somas at different orthogonal levels depending on the cell cycle stage they are. The finding that important regulators of neurogenesis, such as the proneural and neurogenic genes, undergo cyclic changes of expression and function in coordination with the cell cycle and the INM, and that the neurogenic process correlates with a particular window of the cell cycle, in coincidence with the apical localization in the neuroepithelium of neural precursors, is a novel concept that facilitates our understanding of the neurogenic process in vertebrates. As such, recent data support the notion that the three-dimensional structure of the neuroepithelium is crucial for proper neuronal production. In this review, we describe current knowledge of the molecular mechanisms involved in the differential expression and function of the proneural and neurogenic gene products along the cell cycle, and we discuss important consequences for vertebrate neurogenesis derived from this observation. © 2009 UBC Press.Peer Reviewe
Sox2-mediated differential activation of Six3.2 contributes to forebrain patterning
The vertebrate forebrain is patterned during gastrulation into telencephalic, retinal, hypothalamic and diencephalic primordia. Specification of each of these domains requires the concerted activity of combinations of transcription factors (TFs). Paradoxically, some of these factors are widely expressed in the forebrain, which raises the question of how they can mediate regional differences. To address this issue, we focused on the homeobox TF Six3.2. With genomic and functional approaches we demonstrate that, in medaka fish, Six3.2 regulates, in a concentration-dependent manner, telencephalic and retinal specification under the direct control of Sox2. Six3.2 and Sox2 have antagonistic functions in hypothalamic development. These activities are, in part, executed by Foxg1 and Rx3, which seem to be differentially and directly regulated by Six3.2 and Sox2. Together, these data delineate the mechanisms by which Six3.2 diversifies its activity in the forebrain and highlight a novel function for Sox2 as one of the main regulators of anterior forebrain development. They also demonstrate that graded levels of the same TF, probably operating in partially independent transcriptional networks, pattern the vertebrate forebrain along the anterior-posterior axis. © 2012. Published by The Company of Biologists Ltd.Spanish Ministry of Science and Innovation (BFU2007-61774, BFU2010-16031); Comunidad Autonoma de Madrid (P-SAL-0190-2006); Centre for Biomedical Network Research on Rare DiseasesPeer Reviewe
Instability of Notch1 and Delta1 mRNAs and reduced Notch activity in vertebrate neuroepithelial cells undergoing S-phase
Vertebrate neurogenesis is controlled through lateral inhibitory signals triggered by the Notch receptor and its ligand Delta. In the E4 chick embryo, the capacity of neural precursors to express the neurogenic genes Notch1 and Delta1 becomes reduced during S-phase, suggesting that their competence to trigger lateral inhibitory signals varies at different stages of the cell cycle. Here we show that the reduction of neurogenic gene expression during S-phase is extensive to later developmental stages and to other species; and it correlates with lower expression of lunatic Fringe and diminished capability to induce the expression of cHairy1/Hes1 and Hes5-1. We also show that the cell cycle-dependence of Notch1 and Delta1 expression is due to a remarkable decrease of mRNA stability during S-phase. These results provide evidence that the capacity of vertebrate neural precursors to express neurogenic genes and trigger lateral inhibitory signals is functionally coordinated with the cell cycle. © 2008 Elsevier Inc. All rights reserved.This work was supported by the Ministerio de Ciencia y Tecnología (BCM2003-03441/BFU2006-00805), Fundacion “La Caixa” (BM05-71-0), and FUNDALUCE.Peer Reviewe
Beyond Wnt inhibition: New functions of secreted Frizzled-related proteins in development and disease
The secreted Frizzled-related proteins (SFRPs) are a family of soluble proteins that are structurally related to Frizzled (Fz) proteins, the serpentine receptors that mediate the extensively used cell-cell communication pathway involving Wnt signalling. Because of their homology with the Wnt-binding domain on the Fz receptors, SFRPs were immediately characterised as antagonists that bind to Wnt proteins to prevent signal activation. Since these initial studies, interest in the family of SFRPs has grown progressively, offering new perspectives on their function and mechanism of action in both development and disease. These studies indicate that SFRPs are not merely Wnt-binding proteins, but can also antagonise one another's activity, bind to Fz receptors and influence axon guidance, interfere with BMIP signalling by acting as proteinase inhibitors, and interact with other receptors or matrix molecules. Furthermore, their expression is altered in different types of cancers, bone pathologies, retinal degeneration and hypophosphatemic diseases, indicating that their activity is fundamental for tissue homeostasis. Here we review some of the debated aspects of SFRP-Wnt interactions and discuss the new and emerging roles of SFRPs.Peer Reviewe
Cux1 and Cux2 Regulate Dendritic Branching, Spine Morphology, and Synapses of the Upper Layer Neurons of the Cortex
13 páginas, 8 figuras.-- PMCID: PMC2894581Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular, and electrophysiological analysis, we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development, and synapse formation in layer II-III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits.This work was supported by MICINN grants (SAF2005-0094,
SAF2008-00211, PIE-200820I166, and BFU2007-61774), a grant from Mutua
Madrilen˜ a Automovilı´stica (0328-2005), and a grant from the Spanish Comunidad
de Madrid CCG08-CSIC/SAL-3464. B. Cubelos holds a fellowship from
the CSIC (JAEDoc2008-020), and A. Sebastian-Serrano, from the MICINN
(BES-2006-13901). C.A.W. was supported by 2RO1 NS032457 from the
NINDS, and J.M. Redondo, by grant SAF2006-08348. C.A.W. is an Investigator
of the Howard Hughes Medical Institute. The Centro Nacional de Investigaciones
Cardiovasculares is supported by the MICINN and the Pro-CNIC
Foundation.Peer reviewe