Biomedical subjects

Salvador Martinez

Publications and source records attributed to Salvador Martinez.

14 recordsLinked to original sources

PubMed2006

Adult stem cell therapy: dream or reality?

Adult stem cells may be an invaluable source of plastic cells for tissue regeneration. The bone marrow contains different subpopulations of adult stem cells easily accessible for transplantation. However the therapeutic value of adult stem cell is a question of debate in the scientific community. We have investigated the potential benefits of adult hematopoietic stem cell transplantation in animal models of demyelinating and motor neuron diseases. Our results suggest that transplantation of HSC have direct and indirect neuroregenerative and neuroprotective effects.

Animals↗

PubMed2006

The cephalic neural crest exerts a critical effect on forebrain and midbrain development.

Encephalisation is the most important characteristic in the evolutionary transition leading from protochordates to vertebrates. This event has coincided with the emergence of a transient and pluripotent structure, the neural crest (NC), which is absent in protochordates. In vertebrates, NC provides the rostral cephalic vesicles with skeletal protection and functional vascularization. The surgical extirpation of the cephalic NC, which is responsible for building up the craniofacial skeleton, results in the absence of facial skeleton together with severe defects of preotic brain development, leading to exencephaly. Here, we have analyzed the role of the NC in forebrain and midbrain development. We show that (i) NC cells (NCC) control Fgf8 expression in the anterior neural ridge, which is considered the prosencephalic organizer; (ii) the cephalic NCC are necessary for the closure of the neural tube; and (iii) NCC contribute to the proper patterning of genes that are expressed in the prosencephalic and mesencephalic alar plate. Along with the development of the roof plate, NCC also concur to the patterning of the pallial and subpallial structures. We show that the NC-dependent production of FGF8 in anterior neural ridge is able to restrict Shh expression to the ventral prosencephalon. All together, these findings support the notion that the cephalic NC controls the formation of craniofacial structures and the development of preotic brain.

Animals↗

PubMed2006

A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.

Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.

Animals↗

PubMed2006

Dose-dependent functions of Fgf8 in regulating telencephalic patterning centers.

Mouse embryos bearing hypomorphic and conditional null Fgf8 mutations have small and abnormally patterned telencephalons. We provide evidence that the hypoplasia results from decreased Foxg1 expression, reduced cell proliferation and increased cell death. In addition, alterations in the expression of Bmp4, Wnt8b, Nkx2.1 and Shh are associated with abnormal development of dorsal and ventral structures. Furthermore, nonlinear effects of Fgf8 gene dose on the expression of a subset of genes, including Bmp4 and Msx1, correlate with a holoprosencephaly phenotype and with the nonlinear expression of transcription factors that regulate neocortical patterning. These data suggest that Fgf8 functions to coordinate multiple patterning centers, and that modifications in the relative strength of FGF signaling can have profound effects on the relative size and nature of telencephalic subdivisions.

Alleles↗

PubMed2005

Thalamic development induced by Shh in the chick embryo.

Patterning of the early neural tube is achieved in part by the inductive signals, which arise from neuroepithelial signaling centers. The zona limitans intrathalamica (ZLI) is a neuroepithelial domain in the alar plate of the diencephalon which separates the prethalamus from the thalamus. The ZLI has recently been considered to be a possible secondary organizer, effecting its inductions via sonic hedgehog (Shh), a signaling molecule which drives morphogenetic information for the thalamus. Using experimental embryological techniques involving the generation of chimeric embryos, we show that the formation of the ZLI in the diencephalic alar plate is due to an interaction between the prechordal and epichordal plate neuroepithelia. We also provide evidence that Shh expression in the ZLI underlies the morphogenetic activity of this putative diencephalic organizer. Ectopic Shh led to the auto-induction of its own gene expression in host cells, as well as to the expression of other genes involved in diencephalic regionalization and histogenesis. Analysis of long-term surviving embryos after Shh ectopic expression demonstrated that Shh was able to induce thalamic structures and local overgrowth. Overall, these results indicate that Shh expressed in the ZLI plays an important role in diencephalic growth and in the development of the thalamus.

Acetylcholinesterase↗

PubMed2005

Experimental study of MAP kinase phosphatase-3 (Mkp3) expression in the chick neural tube in relation to Fgf8 activity.

Mitogen-activated protein kinase (MAPK) pathways are well known to be involved in signal transduction from extracellular to intracellular compartments in all eukaryotes. The activation of this cascade will have an effect on cell proliferation, differentiation, and apoptosis. In this study, we describe the cloning of the chick Mkp3 gene that is highly homologous to the mammalian gene and are both expressed in several embryo regions with demonstrated morphogenetic activity. In early developmental stages, Mkp3 and Fgf8 have similar expression patterns. Differences in the activation of Mkp3 transcription in the isthmus and the repression with FGF receptor inhibition suggest that Fgf8 protein controls Mkp3 transcription. Ectopically, expression of Fgf8 protein induces Mkp3 in a short period of time in the diencephalon, indicating a positive regulation of Mkp3 by Fgf8. Moreover, we show a distinct tissue competence to express Mkp3 rostrally and caudally to the zona limitans intrathalamica (ZLI).

Animals↗

PubMed2005

Mkp3 is a negative feedback modulator of Fgf8 signaling in the mammalian isthmic organizer.

The pivotal mechanisms that govern the correct patterning and regionalization of the distinct areas of the mammalian CNS are driven by key molecules that emanate from the so-called secondary organizers at neural plate and tube stages. FGF8 is the candidate morphogenetic molecule to pattern the mesencephalon and rhombencephalon in the isthmic organizer (IsO). Recognizable relevance has been given to the intracellular pathways by which Fgf8 is regulated and modulated. In chick limb bud development, a dual mitogen-activated protein kinase phosphatase-3 (Mkp3) plays a role as a negative feedback modulator of Fgf8 signaling. We have investigated the role of Mkp3 and its functional relationship with the Fgf8 signaling pathway in the mouse IsO using gene transfer microelectroporation assays and protein-soaked bead experiments. Here, we demonstrate that MKP3 has a negative feedback action on the MAPK/ERK-mediated FGF8 pathway in the mouse neuroepithelium.

Animals↗

PubMed2005

Modulation of Fgf8 activity during vertebrate brain development.

In recent years much emphasis has been placed on investigation of the precise control of FGF signaling during brain development. Such control is achieved in part by regulatory elements that determine the domains and levels of expression of genes coding for the diverse FGF ligands via specific molecular signaling pathways. There is new knowledge on the operation of such mechanisms in regions of the neural tube involved in the correct patterning of adjacent territories (known as secondary organizers of neural tube pattern). In the present minireview we intend to summarize recent evidence and emerging conclusions on potent modulators that govern the activity of Fgf8 signals in the developing vertebrate brain, focusing our attention on the best known secondary organizer, the isthmic organizer.

Animals↗

PubMed2004

Fate map of the diencephalon and the zona limitans at the 10-somites stage in chick embryos.

The diencephalon is a central area of the vertebrate developing brain, where the thalamic nuclear complex, the pretectum and the anterior tegmental structures are generated. It has been subdivided into prosomeres, which are transversal domains defined by morphological and molecular criteria. The zona limitans intrathalamica is a central boundary in the diencephalon that separates the posterior diencephalon (prosomeres 1 and 2), from the anterior diencephalon (prosomere 3). This intrathalamic limit appears early on in neural tube development, and the molecular pattern that it reveals suggests an important role in the diencephalic histogenesis. We hereby present a fate map of the presumptive territories in the diencephalon of a chick embryo at the 10-11 somite stages (HH9-10), by homotopic and isochronic quail-chick grafts. The anatomical interpretation of chimeric brains was aided by correlative whole-mount in situ hybridization with RNA probes for chicken genes expressed in specific diencephalic territories. The resulting fate map describes the distribution of the presumptive diencephalic prosomeres in the neural tube, and demonstrates their topologically conserved relationships throughout the neural development. Moreover, we show that the presumptive epithelium of ZLI can be localized at early developmental stages in the diencephalic alar plate at the anterior limit of the Wnt8b gene expression domain.

Animals↗

PubMed2004

PITX2 is required for normal development of neurons in the mouse subthalamic nucleus and midbrain.

Pitx2, a homeodomain transcription factor, is essential for normal development of the pituitary gland, craniofacial region, eyes, heart, abdominal viscera, and limbs. Complete loss of Pitx2 in mice (Pitx2(-/-)) results in embryonic lethality by approximately e15 due to cardiac defects, whereas embryos with partial loss of function (Pitx2(neo/-) or Pitx2(neo/neo)) survive until later in development (e17-e19). Pitx2 is expressed in discrete populations of postmitotic neurons in the mouse brain, but its role in mammalian central nervous system (CNS) development is not known. We undertook an analysis of Pitx2-deficient embryos to determine whether loss of Pitx2 affects CNS development. The CNS is normal in hypomorphic e16.5 Pitx2(neo/-) and e18.5 Pitx2(neo/neo) embryos, with no evidence of midline or other defects. Midgestation (e10.5) Pitx2(-/-) embryos have normally formed neural tube structures and cerebral vesicles, whereas older (e14.5) Pitx2(-/-) embryos exhibit loss of gene expression and axonal projections in the subthalamic nucleus (a group of cells in the ventrolateral thalamus) and in the developing superior colliculus of dorsal midbrain. Our results suggest a role for Pitx2 in regulating regionally specific terminal neuronal differentiation in the developing ventrolateral thalamus and midbrain.

Animals↗

PubMed2004

Analysis of cCx39 expression pattern during chick development.

The present study reports the expression pattern of connexin39 (cCx39) in chick embryos at different stages of central nervous system development. We examined the expression between HH17 and HH40 developmental stages of chicken embryos by in situ hybridization (ISH) technique. Connexin39 was first expressed at HH17. It stained neuroepithelial cells in the optic (OV) and telencephalic (TEL) vesicles, plus in the superficial mesenchyme of the two rostral branchial arches (maxilar and mandibular). These cells probably originated from the neural crest. This expression pattern changed drastically between stages HH17 and HH23, while it showed relatively little modifications from HH23 to HH29. At these times, connexin39 was expressed in three regions: the telencephalic vesicle, the diencephalon and the isthmus. At later stages, HH35 and HH40, connexin39 was mainly expressed in the ventricular epithelium and three cell layers of the stratum griseum and fibrosum superficialis (SGFS) in the optic tectum, as well as in granular and nuclear cells in the cerebellum. In conclusion, the expression pattern of connexin39 in embryonic nervous system is dynamic. This pattern is different from, and in some aspects complementary to, those showed by other connexins during brain development.

Animals↗

PubMed2004

Pcp4l1, a novel gene encoding a Pcp4-like polypeptide, is expressed in specific domains of the developing brain.

We report the cloning of a novel mouse gene (Pcp4l1) that encodes a polypeptide with significant sequence similarity to the Purkinje cell protein 4 gene (Pcp4) and describe its expression pattern during mouse development. Similar to Pcp4, the Pc4l1 gene product is characterized by the presence of an IQ domain and is highly conserved across evolution. RNA in situ hybridization reveals instead that Pcp4l1 has a distinct pattern of expression: it is only expressed in the central nervous system (CNS), and is first detected at E9.5 in the mesencephalic and metencephalic roof plate as well as in the isthmus, in a region that overlaps the expression domains of Pax2, Fgf8 and Wnt1. Thus, the early Pcp4l1 expression pattern coincides with the regional expression of well-characterized patterning molecules in the organizing centers of the developing brain. Starting at midgestation, Pcp4l1 is mainly expressed in the structures of the circumventricular organs, including the subcommissural organ, the rhombencephalic and telencephalic choroid plexi, and the pineal gland. In the adult brain, this transcript is also detected in laminar as well as in several nuclear structures of the CNS.

Amino Acid Motifs↗

PubMed2003

The isthmic organizer signal FGF8 is required for cell survival in the prospective midbrain and cerebellum.

Numerous studies have demonstrated that the midbrain and cerebellum develop from a region of the early neural tube comprising two distinct territories known as the mesencephalon (mes) and rostral metencephalon (met; rhombomere 1), respectively. Development of the mes and met is thought to be regulated by molecules produced by a signaling center, termed the isthmic organizer (IsO), which is localized at the boundary between them. FGF8 and WNT1 have been implicated as key components of IsO signaling activity, and previous studies have shown that in Wnt1(-/-) embryos, the mes/met is deleted by the 30 somite stage ( approximately E10) (McMahon, A. P. and Bradley, A. (1990) Cell 62, 1073-1085). We have studied the function of FGF8 in mouse mes/met development using a conditional gene inactivation approach. In our mutant embryos, Fgf8 expression was transiently detected, but then was eliminated in the mes/met by the 10 somite stage ( approximately E8.75). This resulted in a failure to maintain expression of Wnt1 as well as Fgf17, Fgf18, and Gbx2 in the mes/met at early somite stages, and in the absence of the midbrain and cerebellum at E17.5. We show that a major cause of the deletion of these structures is ectopic cell death in the mes/met between the 7 and 30 somite stages. Interestingly, we found that the prospective midbrain was deleted at an earlier stage than the prospective cerebellum. We observed a remarkably similar pattern of cell death in Wnt1 null homozygotes, and also detected ectopic mes/met cell death in En1 null homozygotes. Our data show that Fgf8 is part of a complex gene regulatory network that is essential for cell survival in the mes/met.

Animals↗

PubMed1989

Rostral Cerebellum Originates from the Caudal Portion of the So-Called 'Mesencephalic' Vesicle: A Study Using Chick/Quail Chimeras.

Homotopic and isochronic transplantations of the right dorsal half of the mesencephalic vesicle have been performed between chick and quail embryos at the stage of 10 - 14 somites. Analysis of the extension of the graft, by means of the quail nucleolar marker, combined with cytoarchitectonic analysis has disclosed that the transplanted neuroepithelium gives rise to isthmic nuclei and to a portion of rostral cerebellum, in addition to the optic tectum and mesencephalic dorsal grisea. These results show that the rostral portion of the cerebellar primordium is located in the so-called 'mesencephalic' alar plate, thus considerably more rostrally than previously supposed. This has been confirmed by two other types of chimeric embryos resulting from homotopic transplantation of either: (i) the quail right alar plate of the first rhombencephalic vesicle, which gives rise to caudal but not rostral cerebellum in the operated side, or (ii) the right alar portion of a segment of the quail neural tube including both the caudal third of the mesencephalic vesicle and the rostral half of the first rhombencephalic vesicle, which gives rise to the whole hemicerebellum in the operated side. Moreover, in chimeric embryos with transplants restricted to the mesencephalic alar plate, the grafted portion of the cerebellar primordium gives rise both to deep cerebellar neurons and to all types of cortical neurons. Among the quail cortical neurons, the Purkinje cells, although intermingled with host Purkinje cells, are organized, at E18, in a characteristic longitudinal band which is strongly reminiscent of the longitudinal functional and morphological organization of the cerebellum. Other types of quail cortical neurons, that is, Golgi cells, granule cells, and molecular layer interneurons, are also observed within this sagittal band. In addition, quail granule cells and molecular layer interneurons as well as quail glial cells, extend over a larger territory on both sides of the longitudinal band containing quail Purkinje cells and even cross the midline and invade the contralateral hemicerebellum. In all types of chimeric embryos, the proliferation, migration, and differentiation of quail transplanted neurons, both in the isthmic region and in the cerebellum, evolve asynchronously from the host homologous ones, following a more precocious and faster developmental schedule. This asynchrony in the development of grafted and host isthmic and cerebellar homologous areas confirms and extends previous findings concerning the proliferation and migration of quail tectal cells in chick quail chimeric embryos (Senut and Alvarado-Mallart, 1987).

Journal Article↗