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1.
Clin Genet ; 104(6): 637-647, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37702321

RESUMEN

Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.


Asunto(s)
Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Trastorno del Espectro Autista/genética , Estudios Prospectivos , Haploinsuficiencia , Síndrome , Fenotipo , Factores de Transcripción SOXD/genética
2.
Hum Mol Genet ; 26(23): 4556-4571, 2017 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-28973407

RESUMEN

GLI1, GLI2 and GLI3 form a family of transcription factors which regulate development by mediating the action of Hedgehog (Hh) morphogens. Accordingly, inactivating variants in GLI2 and GLI3 are found in several developmental disorders. In contrast, loss-of-function mutations in GLI1 have remained elusive, maintaining enigmatic the role of this gene in the human embryo. We describe eight patients from three independent families having biallelic truncating variants in GLI1 and developmental defects overlapping with Ellis-van Creveld syndrome (EvC), a disease caused by diminished Hh signaling. Two families had mutations in the last exon of the gene and a third family was identified with an N-terminal stop gain variant predicted to be degraded by the NMD-pathway. Analysis of fibroblasts from one of the patients with homozygous C-terminal truncation of GLI1 demonstrated that the corresponding mutant GLI1 protein is fabricated by patient cells and becomes upregulated in response to Hh signaling. However, the transcriptional activity of the truncated GLI1 factor was found to be severely impaired by cell culture and in vivo assays, indicating that the balance between GLI repressors and activators is altered in affected subjects. Consistent with this, reduced expression of the GLI target PTCH1 was observed in patient fibroblasts after chemical induction of the Hh pathway. We conclude that GLI1 inactivation is associated with a phenotypic spectrum extending from isolated postaxial polydactyly to an EvC-like condition.


Asunto(s)
Síndrome de Ellis-Van Creveld/genética , Proteína con Dedos de Zinc GLI1/genética , Niño , Síndrome de Ellis-Van Creveld/metabolismo , Síndrome de Ellis-Van Creveld/patología , Exones , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación del Desarrollo de la Expresión Génica , Silenciador del Gen , Proteínas Hedgehog/metabolismo , Humanos , Lactante , Recién Nacido , Masculino , Linaje , Fenotipo , Polidactilia/genética , Polidactilia/metabolismo , Cultivo Primario de Células , Transducción de Señal , Transactivadores/genética , Transcripción Genética , Proteína con Dedos de Zinc GLI1/metabolismo
3.
Stem Cells ; 34(8): 2194-209, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27144663

RESUMEN

The specific actions of insulin-like growth factor-I (IGF-I) and the role of brain-derived IGF-I during hippocampal neurogenesis have not been fully defined. To address the influence of IGF-I on the stages of hippocampal neurogenesis, we studied a postnatal/adult global Igf-I knockout (KO) mice (Igf-I(-/-) ) and a nervous system Igf-I conditional KO (Igf-I(Δ/Δ) ). In both KO mice we found an accumulation of Tbr2(+) -intermediate neuronal progenitors, some of which were displaced in the outer granule cell layer (GCL) and the molecular layer (ML) of the dentate gyrus (DG). Similarly, more ectopic Ki67(+) - cycling cells were detected. Thus, the GCL was disorganized with significant numbers of Prox1(+) -granule neurons outside this layer and altered morphology of radial glial cells (RGCs). Dividing progenitors were also generated in greater numbers in clonal hippocampal stem cell (HPSC) cultures from the KO mice. Indeed, higher levels of Hes5 and Ngn2, transcription factors that maintain the stem and progenitor cell state, were expressed in both HPSCs and the GCL-ML from the Igf-I(Δ/Δ) mice. To determine the impact of Igf-I deletion on neuronal generation in vivo, progenitors in Igf-I(-/-) and Igf-I(+/+) mice were labeled with a GFP-expressing vector. This revealed that in the Igf-I(-/-) mice more GFP(+) -immature neurons were formed and they had less complex dendritic trees. These findings indicate that local IGF-I plays critical roles during postnatal/adult hippocampal neurogenesis, regulating the transition from HPSCs and progenitors to mature granule neurons in a cell stage-dependent manner. Stem Cells 2016;34:2194-2209.


Asunto(s)
Envejecimiento/metabolismo , Diferenciación Celular , Hipocampo/citología , Hipocampo/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Células-Madre Neurales/citología , Neurogénesis , Neuronas/citología , Animales , Animales Recién Nacidos , Recuento de Células , Ciclo Celular/genética , Diferenciación Celular/genética , Proliferación Celular , Forma de la Célula , Células Clonales , Giro Dentado/citología , Proteínas de Dominio Doblecortina , Eliminación de Gen , Perfilación de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismo , Células-Madre Neurales/metabolismo , Neurogénesis/genética , Neuronas/metabolismo , Neuropéptidos/metabolismo , Receptor IGF Tipo 1/metabolismo , Proteínas Supresoras de Tumor/metabolismo
4.
EMBO Rep ; 11(6): 466-72, 2010 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-20448664

RESUMEN

Genes of the SOX family of high-mobility group transcription factors are essential during nervous system development. In this study, we show that SOX5 is expressed by neural progenitors in the chick spinal cord and is turned off as differentiation proceeds. The overexpression of SOX5 in neural progenitors causes premature cell cycle exit and prevents terminal differentiation. Conversely, knocking down SOX5 protein extends the proliferative period of neural progenitors and causes marked cell death in a dorsal interneuron (dI3) population. Furthermore, SOX5 reduces WNT-beta-catenin signalling, thereby triggering the expression of the negative regulator of the pathway axin2. We propose that SOX5 regulates the timing of cell cycle exit by opposing WNT-beta-catenin activity on cell cycle progression.


Asunto(s)
Ciclo Celular , Neuronas/citología , Factores de Transcripción SOXD/metabolismo , Transducción de Señal , Células Madre/metabolismo , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Ciclo Celular/genética , Diferenciación Celular/genética , Embrión de Pollo , Regulación hacia Abajo/genética , Regulación del Desarrollo de la Expresión Génica , Interneuronas/citología , Interneuronas/metabolismo , Factores de Transcripción SOXD/genética , Médula Espinal/citología , Médula Espinal/embriología , Médula Espinal/metabolismo , Células Madre/citología , Factores de Tiempo , beta Catenina/genética
5.
Cell Rep ; 38(5): 110313, 2022 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-35108528

RESUMEN

The adult neurogenic niche in the hippocampus is maintained through activation of reversibly quiescent neural stem cells (NSCs) with radial glia-like morphology (RGLs). Here, we show that the expression of SoxD transcription factors Sox5 and Sox6 is enriched in activated RGLs. Using inducible deletion of Sox5 or Sox6 in the adult mouse brain, we show that both genes are required for RGL activation and the generation of new neurons. Conversely, Sox5 overexpression in cultured NSCs interferes with entry in quiescence. Mechanistically, expression of the proneural protein Ascl1 (a key RGL regulator) is severely downregulated in SoxD-deficient RGLs, and Ascl1 transcription relies on conserved Sox motifs. Additionally, loss of Sox5 hinders the RGL activation driven by neurogenic stimuli such as environmental enrichment. Altogether, our data suggest that SoxD genes are key mediators in the transition of adult RGLs from quiescence to an activated mitotic state under physiological situations.


Asunto(s)
Células Madre Adultas/metabolismo , Células-Madre Neurales/metabolismo , Factores de Transcripción SOXD/metabolismo , Animales , Diferenciación Celular/fisiología , Hipocampo/metabolismo , Ratones Transgénicos , Neurogénesis/fisiología , Factores de Transcripción SOXD/genética , Factores de Transcripción/metabolismo
6.
Cell Rep ; 35(10): 109229, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34107264

RESUMEN

Hippocampal sclerosis, the major neuropathological hallmark of temporal lobe epilepsy, is characterized by different patterns of neuronal loss. The mechanisms of cell-type-specific vulnerability and their progression and histopathological classification remain controversial. Using single-cell electrophysiology in vivo and immediate-early gene expression, we reveal that superficial CA1 pyramidal neurons are overactive in epileptic rodents. Bulk tissue and single-nucleus expression profiling disclose sublayer-specific transcriptomic signatures and robust microglial pro-inflammatory responses. Transcripts regulating neuronal processes such as voltage channels, synaptic signaling, and cell adhesion are deregulated differently by epilepsy across sublayers, whereas neurodegenerative signatures primarily involve superficial cells. Pseudotime analysis of gene expression in single nuclei and in situ validation reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.


Asunto(s)
Epilepsia/patología , Hipocampo/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Neuronas/patología , Esclerosis/genética , Animales , Humanos , Ratones
7.
J Med Chem ; 63(5): 2638-2655, 2020 03 12.
Artículo en Inglés | MEDLINE | ID: mdl-31825616

RESUMEN

Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/ß-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation toward neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.


Asunto(s)
Benzotiazoles/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Oligodendroglía/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Vía de Señalización Wnt/efectos de los fármacos , Animales , Benzotiazoles/química , Células Cultivadas , Femenino , Humanos , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Neurogénesis/efectos de los fármacos , Oligodendroglía/citología , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/metabolismo , Inhibidores de Proteínas Quinasas/química
8.
Dev Cell ; 3(1): 63-74, 2002 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-12110168

RESUMEN

A molecular oscillator regulates the pace of vertebrate segmentation. Here, we show that the oscillator (clock) controls cyclic initiation of transcription in the unsegmented presomitic mesoderm (PSM). We identify an evolutionarily conserved 2.3 kb region in the murine Lunatic fringe (Lfng) promoter that drives periodic expression in the PSM. This region includes conserved blocks required for enhancing and repressing cyclic Lfng transcription, and to prevent continued expression in formed somites. We also show that dynamic expression in the cycling PSM is lost in the total absence of Notch signaling, and that Notch signaling acts directly via CBF1/RBP-Jkappa binding sites to regulate Lfng. These results are consistent with a model in which oscillatory Notch signaling underlies the segmentation clock and directly activates and indirectly represses Lfng expression.


Asunto(s)
Relojes Biológicos/genética , Tipificación del Cuerpo/genética , Embrión de Mamíferos/embriología , Elementos de Facilitación Genéticos/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Glicosiltransferasas/genética , Proteínas de la Membrana/genética , Activación Transcripcional/genética , Animales , Proteínas Aviares , Embrión de Pollo , Embrión de Mamíferos/citología , Embrión de Mamíferos/metabolismo , Evolución Molecular , Genes Reporteros/genética , Glicosiltransferasas/metabolismo , Mesodermo/citología , Mesodermo/metabolismo , Ratones , Ratones Transgénicos , Datos de Secuencia Molecular , Fragmentos de Péptidos/genética , Fragmentos de Péptidos/metabolismo , Periodicidad , Regiones Promotoras Genéticas/genética , Unión Proteica/genética , Receptores Notch , Homología de Secuencia de Aminoácido , Homología de Secuencia de Ácido Nucleico , Transcripción Genética/fisiología , beta-Galactosidasa/genética , beta-Galactosidasa/metabolismo
9.
Front Cell Dev Biol ; 7: 96, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31214589

RESUMEN

The generation of new neurons is a lifelong process in many vertebrate species that provides an extra level of plasticity to several brain circuits. Frequently, neurogenesis in the adult brain is considered a continuation of earlier developmental processes as it relies in the persistence of neural stem cells, similar to radial glia, known as radial glia-like cells (RGLs). However, adult RGLs are not just leftovers of progenitors that remain in hidden niches in the brain after development has finished. Rather, they seem to be specified and set aside at specific times and places during embryonic and postnatal development. The adult RGLs present several cellular and molecular properties that differ from those observed in developmental radial glial cells such as an extended cell cycle length, acquisition of a quiescence state, a more restricted multipotency and distinct transcriptomic programs underlying those cellular processes. In this minireview, we will discuss the recent attempts to determine how, when and where are the adult RGLs specified.

10.
ACS Chem Neurosci ; 10(1): 279-294, 2019 01 16.
Artículo en Inglés | MEDLINE | ID: mdl-30253086

RESUMEN

Overcoming the lack of effective treatments and the continuous clinical trial failures in neurodegenerative drug discovery might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting simultaneously neuroprotection and neuroregeneration. In the studies reported herein, we sought to identify small molecules that might exert neuroprotective and neuroregenerative potential as tools against neurodegenerative diseases. In doing so, we started from the reported neuroprotective/neuroregenerative mechanisms of psychotropic drugs featuring a tricyclic alkylamine scaffold. Thus, we designed a focused-chemical library of 36 entries aimed at exploring the structural requirements for efficient neuroprotective/neuroregenerative cellular activity, without the manifestation of toxicity. To this aim, we developed a synthetic protocol, which overcame the limited applicability of previously reported procedures. Next, we evaluated the synthesized compounds through a phenotypic screening pipeline, based on primary neuronal systems. Phenothiazine 2Bc showed improved neuroregenerative and neuroprotective properties with respect to reference drug desipramine (2Aa). Importantly, we have also shown that 2Bc outperformed currently available drugs in cell models of Alzheimer's and Parkinson's diseases and attenuates microglial activation by reducing iNOS expression.


Asunto(s)
Descubrimiento de Drogas/métodos , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/química , Fármacos Neuroprotectores/farmacología , Psicotrópicos/química , Psicotrópicos/farmacología , Animales , Animales Recién Nacidos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Corteza Cerebral/citología , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/fisiología , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Regeneración Nerviosa/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar
11.
Front Cell Dev Biol ; 5: 58, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28626748

RESUMEN

During vertebrate embryonic development, the spinal cord is formed by the neural derivatives of a neuromesodermal population that is specified at early stages of development and which develops in concert with the caudal regression of the primitive streak. Several processes related to spinal cord specification and maturation are coupled to this caudal extension including neurogenesis, ventral patterning and neural crest specification and all of them seem to be crucially regulated by Fibroblast Growth Factor (FGF) signaling, which is prominently active in the neuromesodermal region and transiently in its derivatives. Here we review the role of FGF signaling in those processes, trying to separate its different functions and highlighting the interactions with other signaling pathways. Finally, these early functions of FGF signaling in spinal cord development may underlay partly its ability to promote regeneration in the lesioned spinal cord as well as its action promoting specific fates in neural stem cell cultures that may be used for therapeutical purposes.

12.
Eur J Med Chem ; 138: 328-342, 2017 Sep 29.
Artículo en Inglés | MEDLINE | ID: mdl-28688273

RESUMEN

Leucine-rich repeat kinase 2 (LRRK2) is one of the most pursued targets for Parkinson's disease (PD) therapy. Moreover, it has recently described its role in regulating Wnt signaling and thus, it may be involved in adult neurogenesis. This new hypothesis could give rise to double disease-modifying agents firstly by the benefits of inhibiting LRRK2 and secondly by promoting adult neurogenesis. Herein we report, the design, synthesis, biological evaluation, SAR and potential binding mode of indoline-like LRRK2 inhibitors and their preliminary neurogenic effect in neural precursor cells isolated from adult mice ventricular-subventricular zone. These results open new therapeutic horizons for the use of LRRK2 inhibitors as neuroregenerative agents. Moreover, the indolinone derivatives here prepared, inhibitors of the kinase activity of LRRK2, may be considered as pharmacological probes to study the potential neuroregeneration of the damaged brain.


Asunto(s)
Indoles/farmacología , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/antagonistas & inhibidores , Células-Madre Neurales/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Humanos , Indoles/síntesis química , Indoles/química , Proteína 2 Quinasa Serina-Treonina Rica en Repeticiones de Leucina/metabolismo , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , Estructura Molecular , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Relación Estructura-Actividad
13.
Dev Neurobiol ; 76(9): 956-71, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26600420

RESUMEN

A prevalent developmental mechanism for the assignment of cell identities is the production of spatiotemporal concentration gradients of extracellular signaling molecules that are interpreted by the responding cells. One of such signaling systems is the Shh gradient that controls neuronal subtype identity in the ventral spinal cord. Using loss and gain of function approaches in chick and mouse embryos, we show here that the fibroblast growth factor (FGF) signaling pathway is required to restrict the domains of ventral gene expression as neuroepithelial cells become exposed to Shh during caudal extension of the embryo. FGF signaling activates the expression of the Shh receptor and negative pathway regulator Patched 2 (Ptch2) and therefore can enhance a negative feedback loop that restrains the activity of the pathway. Thus, we identify one of the mechanisms by which FGF signaling acts as a modulator of the onset of Shh signaling activity in the context of coordination of ventral patterning and caudal axis extension. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 956-971, 2016.


Asunto(s)
Factores de Crecimiento de Fibroblastos/fisiología , Regulación del Desarrollo de la Expresión Génica/fisiología , Proteínas Hedgehog/fisiología , Transducción de Señal/fisiología , Asta Ventral de la Médula Espinal/fisiología , Animales , Embrión de Pollo , Humanos , Ratones , Asta Ventral de la Médula Espinal/embriología
15.
Dev Neurobiol ; 75(5): 522-38, 2015 May.
Artículo en Inglés | MEDLINE | ID: mdl-25363628

RESUMEN

The basic organization of somatosensory circuits in the spinal cord is already setup during the initial patterning of the dorsal neural tube. Extrinsic signals, such as Wnt and TGF-ß pathways, activate combinatorial codes of transcription factors that are responsible for generating a pattern of discrete domains of dorsal progenitors (dp). These progenitors will give rise to distinct dorsal interneurons (dI). The Wnt/ ßcatenin signaling pathway controls specification of dp/dI1-3 progenitors and interneurons. According to the current model in the field, Wnt/ßcatenin activity seems to act in a graded fashion in the spinal cord, as different relative levels determine the identity of adjacent progenitors. However, it is not clear how this activity gradient is controlled and how the identities of dI1-3 are differentially regulated by Wnt signalling. We have determined that two SoxD transcription factors, Sox5 and Sox6, are expressed in restricted domains of dorsal progenitors in the neural tube. Using gain- and loss-of function approaches in chicken embryos, we have established that Sox5 controls cell fate specification of dp2 and dp3 progenitors and, as a result, controls the correct number of the corresponding dorsal interneurons (dI2 and dI3). Furthermore, Sox5 exerts its function by restricting dorsally Wnt signaling activity via direct transcriptional induction of the negative Wnt pathway regulator Axin2. By that way, Sox5 acts as a Wnt pathway modulator that contributes to sharpen the dorsal gradient of Wnt/ßcatenin activity to control the distinction of two functionally distinct types of interneurons, dI2 and dI3 involved in the somatosensory relay.


Asunto(s)
Proteínas Aviares/metabolismo , Regulación del Desarrollo de la Expresión Génica/fisiología , Interneuronas/citología , Factores de Transcripción SOXD/metabolismo , Médula Espinal/metabolismo , Células Madre/citología , Animales , Proteínas Aviares/genética , Diferenciación Celular/fisiología , Embrión de Pollo , Pollos , Factores de Transcripción SOXD/genética , Transducción de Señal/genética , Médula Espinal/embriología , Proteínas Wnt/metabolismo
16.
J Cell Biol ; 194(3): 489-503, 2011 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-21807879

RESUMEN

Coordination between functionally related adjacent tissues is essential during development. For example, formation of trunk neural crest cells (NCCs) is highly influenced by the adjacent mesoderm, but the molecular mechanism involved is not well understood. As part of this mechanism, fibroblast growth factor (FGF) and retinoic acid (RA) mesodermal gradients control the onset of neurogenesis in the extending neural tube. In this paper, using gain- and loss-of-function experiments, we show that caudal FGF signaling prevents premature specification of NCCs and, consequently, premature epithelial-mesenchymal transition (EMT) to allow cell emigration. In contrast, rostrally generated RA promotes EMT of NCCs at somitic levels. Furthermore, we show that FGF and RA signaling control EMT in part through the modulation of elements of the bone morphogenetic protein and Wnt signaling pathways. These data establish a clear role for opposition of FGF and RA signaling in control of the timing of NCC EMT and emigration and, consequently, coordination of the development of the central and peripheral nervous system during vertebrate trunk elongation.


Asunto(s)
Transición Epitelial-Mesenquimal , Factores de Crecimiento de Fibroblastos/metabolismo , Cresta Neural/citología , Tretinoina/metabolismo , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Morfogenéticas Óseas/fisiología , Ciclo Celular , Movimiento Celular , Sistema Nervioso Central/embriología , Embrión de Pollo , Electroporación , Transición Epitelial-Mesenquimal/genética , Regulación del Desarrollo de la Expresión Génica , Sistema de Señalización de MAP Quinasas , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Cresta Neural/metabolismo , Cresta Neural/fisiología , Sistema Nervioso Periférico/embriología , Reacción en Cadena de la Polimerasa , Transducción de Señal , Factores de Transcripción/biosíntesis , Proteínas Wnt/metabolismo
17.
Dev Dyn ; 236(9): 2702-7, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17685482

RESUMEN

Sox5 is a member of the SoxD group of HMG-box transcription factors that, during the early stages of development, promotes neural crest generation. However, little is known about Sox5 function in neural crest derivatives such as the peripheral sensory nervous system. We have analysed the embryonic expression of Sox5 during chick cranial ganglia development, from the stages of ganglia condensation to those of differentiation. During this period, Sox5 expression is maintained in the crest-derived satellite glial cells in all the cranial ganglia. In contrast, Sox5 is only transiently expressed in a subpopulation of differentiating neurons of both neural crest and placode origin. This detailed analysis provides a good base to dissect the possible role of Sox5 in neural cell fate determination by future functional approaches.


Asunto(s)
Encéfalo/embriología , Ganglios/embriología , Regulación del Desarrollo de la Expresión Génica , Proteínas HMGB/biosíntesis , Proteínas HMGB/genética , Neuroglía/metabolismo , Animales , Diferenciación Celular , Linaje de la Célula , Embrión de Pollo , Proteínas de Unión al ADN/biosíntesis , Perfilación de la Expresión Génica , Proteínas del Grupo de Alta Movilidad/biosíntesis , Inmunohistoquímica , Cresta Neural/embriología , Factores de Transcripción SOXE , Factores de Transcripción/biosíntesis , Ganglio del Trigémino/embriología
18.
EMBO Rep ; 8(1): 104-9, 2007 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-17124510

RESUMEN

Retinoic acid (RA) signalling ensures that vertebrate mesoderm segmentation is bilaterally synchronized, and corrects transient interferences from asymmetric left-right (L-R) signals involved in organ lateralization. Snail genes participate in both these processes and, although they are expressed symmetrically in the presomitic mesoderm (PSM), Snail1 transcripts are asymmetrically distributed in the L-R lateral mesoderm. We show that the alteration of the symmetric Snail expression in the PSM induces asynchronous somite formation. Furthermore, in the absence of RA signalling, normal asymmetric Snail1 expression in the lateral mesoderm is extended to the PSM, desynchronizing somitogenesis. Thus, Snail1 is the first cue corrected by RA in the PSM to ensure synchronized bilateral segmentation.


Asunto(s)
Tipificación del Cuerpo/genética , Desarrollo Embrionario/genética , Somitos/metabolismo , Factores de Transcripción/genética , Animales , Tipificación del Cuerpo/efectos de los fármacos , Embrión de Pollo , Expresión Génica/efectos de los fármacos , Mesodermo/química , Mesodermo/metabolismo , Ratones , Ratones Transgénicos , Interferencia de ARN , ARN Mensajero/análisis , ARN Mensajero/metabolismo , Factores de Transcripción de la Familia Snail , Somitos/química , Tretinoina/farmacología
19.
Semin Cell Dev Biol ; 16(6): 655-62, 2005 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-16076557

RESUMEN

The development of the neural crest up to the stage where they leave the neural tube can be observed as a series of concatenated but independent events that involve dorsalization of the neural plate/neural tube, neural crest induction, segregation and stabilization, epithelial to mesenchymal transition and delamination. During all these processes, the nascent neural crest cells are subjected to the influence of different signals and have to overcome competition for cell fate and apoptotic signals. In addition, striking rostrocaudal differences unveil how the regulatory cascades are somehow different but still can lead to the production of bona fide neural crest cells.


Asunto(s)
Cresta Neural/embriología , Animales , Apoptosis , Ciclo Celular , Supervivencia Celular , Regulación del Desarrollo de la Expresión Génica , Cresta Neural/citología , Cresta Neural/metabolismo , Transducción de Señal
20.
Genes Dev ; 18(10): 1131-43, 2004 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-15155580

RESUMEN

The Snail zinc-finger transcription factors trigger epithelial-mesenchymal transitions (EMTs), endowing epithelial cells with migratory and invasive properties during both embryonic development and tumor progression. During EMT, Snail provokes the loss of epithelial markers, as well as changes in cell shape and the expression of mesenchymal markers. Here, we show that in addition to inducing dramatic phenotypic alterations, Snail attenuates the cell cycle and confers resistance to cell death induced by the withdrawal of survival factors and by pro-apoptotic signals. Hence, Snail favors changes in cell shape versus cell division, indicating that with respect to oncogenesis, although a deregulation/increase in proliferation is crucial for tumor formation and growth, this may not be so for tumor malignization. Finally, the resistance to cell death conferred by Snail provides a selective advantage to embryonic cells to migrate and colonize distant territories, and to malignant cells to separate from the primary tumor, invade, and form metastasis.


Asunto(s)
Ciclo Celular/fisiología , Muerte Celular/fisiología , Proteínas de Unión al ADN/fisiología , Factores de Transcripción/fisiología , Animales , Apoptosis , Secuencia de Bases , Ciclo Celular/genética , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Línea Celular , Embrión de Pollo , Medio de Cultivo Libre de Suero , Ciclina D1/genética , Ciclina D2 , Ciclinas/genética , ADN Complementario/genética , Proteínas de Unión al ADN/genética , Perros , Desarrollo Embrionario y Fetal/genética , Desarrollo Embrionario y Fetal/fisiología , Células Epiteliales/citología , Humanos , Mesodermo/citología , Ratones , Transducción de Señal , Factores de Transcripción de la Familia Snail , Factores de Transcripción/genética , Transcripción Genética , Factor de Necrosis Tumoral alfa/farmacología
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