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Biomedical subjects

J L Rubenstein

Publications and source records attributed to J L Rubenstein.

At least 55 records · Page 3Linked to original sources
PubMed1999

Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum.

The telencephalon is organized into distinct longitudinal domains: the cerebral cortex and the basal ganglia. The basal ganglia primarily consists of a dorsal region (striatum) and a ventral region (pallidum). Within the telencephalon, the anlage of the pallidum expresses the Nkx2.1 homeobox gene. A mouse deficient in Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA-positive neurons (probable cholinergic neurons) and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex. We present evidence that these phenotypes result from a ventral-to-dorsal transformation of the pallidal primordium into a striatal-like anlage.

Animals↗
PubMed1999

Dlx5 regulates regional development of the branchial arches and sensory capsules.

We report the generation and analysis of mice homozygous for a targeted deletion of the Dlx5 homeobox gene. Dlx5 mutant mice have multiple defects in craniofacial structures, including their ears, noses, mandibles and calvaria, and die shortly after birth. A subset (28%) exhibit exencephaly. Ectodermal expression of Dlx5 is required for the development of olfactory and otic placode-derived epithelia and surrounding capsules. The nasal capsules are hypoplastic (e.g. lacking turbinates) and, in most cases, the right side is more severely affected than the left. Dorsal otic vesicle derivatives (e. g. semicircular canals and endolymphatic duct) and the surrounding capsule, are more severely affected than ventral (cochlear) structures. Dlx5 is also required in mandibular arch ectomesenchyme, as the proximal mandibular arch skeleton is dysmorphic. Dlx5 may control craniofacial development in part through the regulation of the goosecoid homeobox gene. goosecoid expression is greatly reduced in Dlx5 mutants, and both goosecoid and Dlx5 mutants share a number of similar craniofacial malformations. Dlx5 may perform a general role in skeletal differentiation, as exemplified by hypomineralization within the calvaria. The distinct focal defects within the branchial arches of the Dlx1, Dlx2 and Dlx5 mutants, along with the nested expression of their RNAs, support a model in which these genes have both redundant and unique functions in the regulation of regional patterning of the craniofacial ectomesenchyme.

Animals↗
PubMed1999

Induction of the epibranchial placodes.

The cranial sensory ganglia, in contrast to those of the trunk, have a dual embryonic origin arising from both neurogenic placodes and neural crest. Neurogenic placodes are focal thickenings of ectoderm, found exclusively in the head of vertebrate embryos. These structures can be split into two groups based on the positions that they occupy within the embryo, dorsolateral and epibranchial. The dorsolateral placodes develop alongside the central nervous system, while the epibranchial placodes are located close to the top of the clefts between the branchial arches. Importantly, previous studies have shown that the neurogenic placodes form under the influence of the surrounding cranial tissues. In this paper, we have analysed the nature of the inductive signal underlying the formation of the epibranchial placodes. We find that epibranchial placodes do not require neural crest for their induction, but rather that it is the pharyngeal endoderm that is the source of the inductive signal. We also find that, while cranial ectoderm is competent to respond to this inductive signal, trunk ectoderm is not. We have further identified the signalling molecule Bmp7 as the mediator of this inductive interaction. This molecule is expressed in a manner consistent with it playing such a role and, when added to ectoderm explants, it will promote the formation of epibranchial neuronal cells. Moreover, the Bmp7 antagonist follstatin will block the ability of pharyngeal endoderm to induce placodal neuronal cells, demonstrating that Bmp7 is required for this inductive interaction. This work answers the long standing question regarding the induction of the epibranchial placodes, and represents the first elucidation of an inductive mechanism, and a molecular effector, underlying the formation of any primary sensory neurons in higher vertebrates.

Animals↗
PubMed1999

FGF8 induces formation of an ectopic isthmic organizer and isthmocerebellar development via a repressive effect on Otx2 expression.

Beads containing recombinant FGF8 (FGF8-beads) were implanted in the prospective caudal diencephalon or midbrain of chick embryos at stages 9-12. This induced the neuroepithelium rostral and caudal to the FGF8-bead to form two ectopic, mirror-image midbrains. Furthermore, cells in direct contact with the bead formed an outgrowth that protruded laterally from the neural tube. Tissue within such lateral outgrowths developed proximally into isthmic nuclei and distally into a cerebellum-like structure. These morphogenetic effects were apparently due to FGF8-mediated changes in gene expression in the vicinity of the bead, including a repressive effect on Otx2 and an inductive effect on En1, Fgf8 and Wnt1 expression. The ectopic Fgf8 and Wnt1 expression domains formed nearly complete concentric rings around the FGF8-bead, with the Wnt1 ring outermost. These observations suggest that FGF8 induces the formation of a ring-like ectopic signaling center (organizer) in the lateral wall of the brain, similar to the one that normally encircles the neural tube at the isthmic constriction, which is located at the boundary between the prospective midbrain and hindbrain. This ectopic isthmic organizer apparently sends long-range patterning signals both rostrally and caudally, resulting in the development of the two ectopic midbrains. Interestingly, our data suggest that these inductive signals spread readily in a caudal direction, but are inhibited from spreading rostrally across diencephalic neuromere boundaries. These results provide insights into the mechanism by which FGF8 induces an ectopic organizer and suggest that a negative feedback loop between Fgf8 and Otx2 plays a key role in patterning the midbrain and anterior hindbrain.

Animals↗
PubMed1998

Development of serotonergic neurons and their projections.

Neurons producing serotonin are among the earliest to be born in the developing central nervous system. These cells are largely restricted to the hindbrain, where there form primarily in ventral regions. This review describes some of the mechanisms that regulate patterning and differentiation of the embryonic brain, which are implicated in neurogenesis of serotonergic neurons. It also covers the development of serotonergic axon pathways and the potential role of serotonin in regulating developmental processes.

Animals↗
PubMed1998

FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate.

During development, distinct classes of neurons are specified in precise locations along the dorso-ventral and anterior-posterior axes of the neural tube. We provide evidence that intersections of Shh, which is expressed along the ventral neural tube, and FGF8, which is locally produced at the mid/hindbrain boundary and in the rostral forebrain, create induction sites for dopaminergic neurons in the midbrain and forebrain. The same intersection, when preceded by a third signal, FGF4, which is expressed in the primitive streak, defines an inductive center for hindbrain 5-HT neurons. These findings illustrate that cell patterning in the neural plate is a multistep process in which early inducers, which initially divide the neural plate into crude compartments, are replaced by multiple local organizing centers, which specify distinct neuronal cell types within these compartments.

Animals↗
PubMed1998

An olfactory sensory map develops in the absence of normal projection neurons or GABAergic interneurons.

Olfactory sensory neurons expressing a given odorant receptor project to two topographically fixed glomeruli in the olfactory bulb. We have examined the contribution of different cell types in the olfactory bulb to the establishment of this topographic map. Mice with a homozygous deficiency in Tbr-1 lack most projection neurons, whereas mice with a homozygous deficiency in Dlx-1 and Dlx-2 lack most GABAergic interneurons. Mice bearing a P2-IRES-tau-lacZ allele and deficient in either Tbr-1 or Dlx-1/Dlx-2 reveal the convergence of axons to one medial and one lateral site at positions analogous to those observed in wild-type mice. These observations suggest that the establishment of a topographic map is not dependent upon cues provided by, or synapse formation with, the major neuronal cell types in the olfactory bulb.

Animals↗
PubMed1998

Control of anteroposterior and dorsoventral domains of Nkx-6.1 gene expression relative to other Nkx genes during vertebrate CNS development.

Here we report the isolation, sequence and developmental expression in the central nervous system of several members of the chicken and mouse Nkx gene family. These are among the earliest genes to be regionally expressed in the neural plate; they are expressed just above the axial mesendoderm (prechordal mesendoderm and notochord). Each Nkx gene has a distinct spatial pattern of expression along the anterior-posterior axis of the ventral central nervous system: Nkx-2. 2 is expressed along the entire axis, whereas Nkx-2.1 is restricted to the forebrain, and Nkx-6.1 and Nkx-6.2 are largely excluded from the forebrain. They are also expressed in distinct patterns along the dorsal-ventral axis. These genes are expressed in both the ventricular and mantle zones; in the mantle zone Nkx-6.1 is co-expressed with Islet-1 in a subset of motor neurons. Like other Nkx genes, expression of Nkx-6.1 is induced by the axial mesendoderm and by sonic hedgehog protein. BMP-7 represses Nkx-6.1 expression. While the notochord can induce Nkx-6.1 expression in the anterior neural plate, sonic hedgehog protein does not, suggesting that the notochord produces additional molecules that can regulate ventral patterning.

Amino Acid Sequence↗
PubMed1998

Patterning of the embryonic forebrain.

The vertebrate forebrain is derived from the anterior neural plate, where anteroposterior, dorsoventral and local patterning mechanisms specify regional identify. The recent identification of genetic regulators of these processes has opened the way to elucidating how the major forebrain regions (i.e. cerebral cortex, basal ganglia, thalamus, and hypothalamus) are formed, and how molecular lesions in these processes cause human birth defects.

Animals↗
PubMed1998

Suicidal behavior in adolescents: stress and protection in different family contexts.

Recent suicidal behavior was reported on a questionnaire by 14% of 272 high school students. Two-thirds of the suicidal teenagers neither received help nor disclosed their self-harm to anyone. Depression and stress--especially family suicidality, feelings of violation, and sexuality--increased the risk, as did parental separation, divorce, and most dramatically, remarriage. Family cohesiveness helped alleviate the risk in the nonintact families.

Adolescent↗
PubMed1998

Association of MSX1 and TGFB3 with nonsyndromic clefting in humans.

Nonsyndromic cleft lip with or without cleft palate (CL/P) and nonsyndromic cleft palate only (CPO) are common congenital anomalies with significant medical, psychological, social, and economic ramifications. Both CL/P and CPO are examples of complex genetic traits. There exists sufficient evidence to hypothesize that disease loci for CL/P and CPO can be identified by a candidate-gene linkage-disequilibrium (LD) strategy. Candidate genes for clefting, including TGFA, BCL3, DLX2, MSX1, and TGFB3, were screened for LD with either CL/P or CPO in a predominantly Caucasian population, with both case-control- and nuclear-family-based approaches. Previously reported LD for TGFA with both CL/P and CPO could not be confirmed, except in CL/P patients with a positive family history. Also, in contrast to previous studies, no LD was found between BCL3 and either CL/P or CPO. Significant LD was found between CL/P and both MSX1 and TGFB3 and between CPO and MSX1, suggesting that these genes are involved in the pathogenesis of clefting. In addition, a mutation search in the genes DLX2, MSX1, and TGFB3 was performed in 69 CPO patients and in a subset of the CL/P patients. No common mutations were found in the coding regions of these genes; however, several rare variants of MSX1 and TGFB3 were found that may alter the latters' normal function. These results form the basis for future research, including (a) mutation searches in the MSX1 and TGFB3 genes in Caucasian CL/P patients and (b) extension of the search for MSX1 mutations in CPO patients to the noncoding regions.

Amino Acid Substitution↗
PubMed1998

Molecular control of odontogenic patterning: positional dependent initiation and morphogenesis.

We have previously proposed that the patterning of the mammalian dentition is determined by an odontogenic homeobox code, whereby positional specification of odontogenic ectomesenchymal cell populations in a given region of the first branchial arch are determined by the combination of different homeobox genes expressed, described in detail in (1). Here we describe the first functional evidence for such a mechanism, and show that development of different types of teeth is controlled by independent genetic pathways. We suggest a mechanism whereby patterning is determined by position dependent control of tooth germ initiation, and propose that the pathway of morphogenesis is directly linked to the early mesenchymal expression of homeobox genes.

Animals↗
PubMed1998

Regionalization of the prosencephalic neural plate.

Recent embryological studies are beginning to establish that the underlying organization of the forebrain may be reduced to relatively simple elements that are common to all vertebrates. We begin this chapter by reviewing studies that describe the similarities in prospective fate and molecular organization of the developing neural plate in fish, frogs, chickens, and mice. The chapter next addresses mechanisms that regulate regional specification in the anterior central nervous system. There is now evidence that the axial mesendoderm anterior to the notochord (the prechordal plate) has a central role in induction of the floor and basal plate primordia (hypothalamus) of the forebrain. Patterning of the anterolateral neural plate (telencephalon) may be regulated by FGF8 produced in the anterior neural ridge. Thus, the synthesis of information from fate mapping and experimental embryological and genetic studies is illuminating the mechanisms that generate the different components of the forebrain.

Animals↗
PubMed1998

Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta cells.

The endocrine pancreas is organized into clusters of cells called islets of Langerhans comprising four well-defined cell types: alpha beta, delta and PP cells. While recent genetic studies indicate that islet development depends on the function of an integrated network of transcription factors, the specific roles of these factors in early cell-type specification and differentiation remain elusive. Nkx2.2 is a member of the mammalian NK2 homeobox transcription factor family that is expressed in the ventral CNS and the pancreas. Within the pancreas, we demonstrate that Nkx2.2 is expressed in alpha, beta and PP cells, but not in delta cells. In addition, we show that mice homozygous for a null mutation of Nkx2.2 develop severe hyperglycemia and die shortly after birth. Immunohistochemical analysis reveals that the mutant embryos lack insulin-producing beta cells and have fewer glucagon-producing alpha cells and PP cells. Remarkably, in the mutants there remains a large population of islet cells that do not produce any of the four endocrine hormones. These cells express some beta cell markers, such as islet amyloid polypeptide and Pdx1, but lack other definitive beta cell markers including glucose transporter 2 and Nkx6.1. We propose that Nkx2.2 is required for the final differentiation of pancreatic beta cells, and in its absence, beta cells are trapped in an incompletely differentiated state.

Animals↗
PubMed1997

Interneuron migration from basal forebrain to neocortex: dependence on Dlx genes.

Although previous analyses indicate that neocortical neurons originate from the cortical proliferative zone, evidence suggests that a subpopulation of neocortical interneurons originates within the subcortical telencephalon. For example, gamma-aminobutyric acid (GABA)-expressing cells migrate in vitro from the subcortical telencephalon into the neocortex. The number of GABA-expressing cells in neocortical slices is reduced by separating the neocortex from the subcortical telencephalon. Finally, mice lacking the homeodomain proteins DLX-1 and DLX-2 show no detectable cell migration from the subcortical telencephalon to the neocortex and also have few GABA-expressing cells in the neocortex.

Animals↗
PubMed1997

Role of the Dlx homeobox genes in proximodistal patterning of the branchial arches: mutations of Dlx-1, Dlx-2, and Dlx-1 and -2 alter morphogenesis of proximal skeletal and soft tissue structures derived from the first and second arches.

The Dlx homeobox gene family is expressed in a complex pattern within the embryonic craniofacial ectoderm and ectomesenchyme. A previous study established that Dlx-2 is essential for development of proximal regions of the murine first and second branchial arches. Here we describe the craniofacial phenotype of mice with mutations in Dlx-1 and Dlx-1 and -2. The skeletal and soft tissue analyses of mice with Dlx-1 and Dlx-1 and -2 mutations provide additional evidence that the Dlx genes regulate proximodistal patterning of the branchial arches. This analysis also elucidates distinct and overlapping roles for Dlx-1 and Dlx-2 in craniofacial development. Furthermore, mice lacking both Dlx-1 and -2 have unique abnormalities, including the absence of maxillary molars. Dlx-1 and -2 are expressed in the proximal and distal first and second arches, yet only the proximal regions are abnormal. The nested expression patterns of Dlx-1, -2, -3, -5, and -6 provide evidence for a model that predicts the region-specific requirements for each gene. Finally, the Dlx-2 and Dlx-1 and -2 mutants have ectopic skull components that resemble bones and cartilages found in phylogenetically more primitive vertebrates.

Animals↗