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Kenneth Campbell

Publications and source records attributed to Kenneth Campbell.

At least 19 recordsLinked to original sources
PubMed2006

Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly.

The telencephalic neuroepithelium (NE) of mammalian brain has an apical-basal polarity that is marked by the positioning of neural progenitors and adherens junctions on the apical/ventricular surface and the ascending of radial glia/progenitor fibers toward the pial/basal surface. The signaling pathway that establishes this apical-basal polarity of NE is not completely understood, but the Rho-family GTPase Cdc42 may play a critical role because it controls cadherin-based intercellular junctions and cell polarity in many species. Here, we tested this hypothesis by a conditional gene-targeting strategy by using the Foxg1-Cre line to delete Cdc42 in the telencephalic neural progenitors in mouse embryos. We found that Cdc42-deletion abolishes the apical localization of PAR6, aPKC, E-cadherin, beta-catenin, and Numb proteins in the NE, and severely impairs the extension of nestin-positive radial fibers. Consequently, neural progenitors were scattered throughout the entire depth of the NE, and the Cdc42-deficient telencephalon failed to bulge or separate into two cerebral hemispheres, resulting in holoprosencephaly. However, neither the midline expression of Sonic hedgehog nor the dorso-ventral patterning of the telencephalon was affected by Cdc42-deletion. Taken together, these results indicate that Cdc42 has an essential role in establishing the apical-basal polarity of the telencephalic NE, which is needed for the expansion and bifurcation of cerebral hemispheres.

Animals↗
PubMed2006

The zinc finger transcription factor Sp8 regulates the generation and diversity of olfactory bulb interneurons.

The molecular mechanisms that regulate the production and diversity of olfactory bulb interneurons remain poorly understood. With the exception of the GABAergic/dopaminergic subtype in the glomerular layer, no information exists concerning the generation of the other subtypes. Here we show that the recently identified zinc finger transcription factor Sp8 is expressed in neurogenic regions, which give rise to olfactory bulb interneurons at embryonic and postnatal time points and remains expressed in the calretinin-expressing and GABAergic/nondopaminergic interneurons of the glomerular layer. Conditional inactivation of Sp8 in the embryonic ventral telencephalon reveals a requirement for the normal generation of these interneuron subtypes. Sp8 conditional mutants exhibit an increase in cell death within the lateral ganglionic eminence and rostral migratory stream. Moreover, mutant neuroblasts/interneurons are misspecified and display abnormal migration patterns in the olfactory bulb, indicating that Sp8 contributes to olfactory bulb interneuron diversity by regulating the survival, migration, and molecular specification of neuroblasts/interneurons.

Animals↗
PubMed2006

Age-related changes in testosterone and SHBG among Turkana males.

To determine age-related changes in biologically available testosterone (T) among men in a subsistence society and their relationship to energetic status, T, sex hormone binding globulin (SHBG) and anthropometric measures were compared among nomadic and settled Turkana pastoralists of northern Kenya. Hormonal measures were available for 104 nomadic men and 72 settled men, estimated ages 20-90 years. Comparison of the two subpopulations revealed significantly higher blood T (32.7+/- 15.1 vs. 23.4+/-15.2 nM) and SHBG (53.8+/- 19.5 vs. 39.7+/- 20.nM) but not free testosterone index (FTI) (65.6+/- 39.3 vs.66.3+/- 45.9) among the nomads. Total blood T did not exhibit a significant linear decline with age in either subgroup, while SHBG values showed a significant linear increase among the nomads. When controlled for energetic status, FTI showed a significant decrease with age among the nomads, but not the settled males. Total blood T was negatively associated with waist circumference among the nomads, but not the settled males. FTI showed a marginally significant negative association with waist circumference, suprailiac skinfold, and % body fat among the nomads but no associations with body composition among the settled group. These results add additional evidence that T is related to energetic status under conditions of negative energy balance and suggest that cross-population variation in the slope of age-related declines in free serum T and salivary T may be related to energetic status through the effects of SHBG.

Adult↗
PubMed2005

A pre-task resting condition neither 'baseline' nor 'zero'.

This study introduce the comparison of a 'reference state' versus a resting condition (zero), defined upon normative developmental equations. We compared pre-task 'resting' data from healthy individuals with the Normative Cuban digital resting EEG-database recently calculated for VARETA (qEEG/VARETA). The results allowed us to state that a 'pre-task resting conditions' exists as a state beyond the 'zero' or 'baseline' condition. The pre-task 'resting' condition is never truly 'at rest', however most of the previous published fMRI/PET studies assumed such a pre-task condition as reference/baseline condition. By defining different 'resting states' by qEEG/VARETA analyses, we have a potential methodology which can define resting state conditions and to be sure that they are consistent when comparing within group analyses across tasks or between groups either void of task or for task specific conditions.

Adult↗
PubMed2005

Cortical neuron specification: it has its time and place.

Cortical neurogenesis is a highly stereotyped process in which progenitor cells generate neurons destined for specific cortical layers depending on the timing of cell cycle exit. Previous work has shown that during corticogenesis, progenitors become progressively restricted in their developmental potential. Recent work has uncovered some of the intrinsic mechanisms that underlie this fate restriction. In addition to timing, new studies suggest that the location of cell cycle exit in the cortical germinal zone may also contribute to cortical neuron specification.

Animals↗
PubMed2004

Homer1a and 1bc levels in the rat somatosensory cortex vary with the time of day and sleep loss.

Homer protein expression is dependent in part on neuronal activity and sleep. Homer1a differs in function from Homer1bc although both are involved in synaptic scaffolding. The effects of sleep loss, time of day and afferent activity on these molecules were investigated. Rats were sacrificed at the midpoint of either their activity or sleep phases and RNA was prepared from somatosensory cortex samples. Homer1a and 1bc mRNA levels were determined by real time PCR. There were greater amounts of both Homer1a and 1bc in night time samples. In controls, there was more Homer1bc than 1a both day and night. Sleep loss upregulated Homer1a in the morning but not at night. Homer1bc was much less affected by manipulations of sleep. Thus, Homer1a may be a state- and activity-dependent synaptic scaling factor.

Animals↗
PubMed2004

The homeobox gene Gsh2 is required for retinoid production in the embryonic mouse telencephalon.

We have examined the role of the homeobox gene Gsh2 in retinoid production and signaling within the ventral telencephalon of mouse embryos. Gsh2 mutants exhibit altered ventral telencephalic development, including a smaller striatum with fewer DARPP-32 neurons than wild types. We show that the expression of the retinoic acid (RA) synthesis enzyme, retinaldehyde dehydrogenase 3 (Raldh3, also known as Aldh1a3), is reduced in the lateral ganglionic eminence (LGE) of Gsh2 mutants. Moreover, using a retinoid reporter cell assay, we found that retinoid production in the Gsh2 mutants is markedly reduced. The striatal defects in Gsh2 mutants are thought to result from ectopic expression of Pax6 in the LGE. Previously, we had shown that removal of Pax6 from the Gsh2 mutant background improves the molecular identity of the LGE in these double mutants; however, Raldh3 expression is not improved. The Pax6;Gsh2 double mutants possess a larger striatum than the Gsh2 mutants, but the disproportionate reduction in DARPP-32 neurons is not improved. These findings suggest that reduced retinoid production in the Gsh2 mutant contributes to the striatal differentiation defects. As RA promotes the expression of DARPP-32 in differentiating LGE cells in vitro, we examined whether exogenous RA can improve striatal neuron differentiation in the Gsh2 mutants. Indeed, RA supplementation of Gsh2 mutants, during the period of striatal neurogenesis, results in a significant increase in DARPP-32 expression. Thus, in addition to the previously described role for Gsh2 to maintain correct molecular identity in the LGE, our results demonstrate a novel requirement of this gene for retinoid production within the ventral telencephalon.

Animals↗
PubMed2003

Tlx controls proliferation and patterning of lateral telencephalic progenitor domains.

We showed previously that the orphan nuclear receptor Tlx is required for the correct establishment of the pallio-subpallial boundary. Loss of Tlx results in a dorsal expansion of ventral markers (e.g., the homeodomain protein GSH2) into the ventralmost pallial region, i.e., the ventral pallium. We also observed a disproportionate reduction in the size of the Tlx mutant lateral ganglionic eminence (LGE) from embryonic day 14.5 onward. Here we show that this reduction is caused, at least in large part, by a proliferation defect. Interestingly, in Tlx mutants, the LGE derivatives are differentially affected. Although the development of the Tlx mutant striatum is compromised, an apparently normal number of olfactory bulb interneurons are observed. Consistent with this observation, we found that Tlx is required for the normal establishment of the ventral LGE that gives rise to striatal projection neurons. This domain is reduced by the dorsal and ventral expansion of molecular markers normally confined to progenitor domains flanking the ventral LGE. Finally, we investigated possible genetic interactions between Gsh2 and Tlx in lateral telencephalic development. Our results show that, although Gsh2 and Tlx have additive effects on striatal development, they differentially regulate the establishment of ventral pallial identity.

Animals↗
PubMed2003

Sp8 is crucial for limb outgrowth and neuropore closure.

In this report we describe the developmental expression and function of Sp8, a member of the Sp family of zinc finger transcription factors, and provide evidence that the legless transgene insertional mutant is a hypomorphic allele of the Sp8 gene. Sp8 is expressed during embryogenesis in the forming apical ectodermal ridge (AER), restricted regions of the central nervous system, and tail bud. Targeted deletion of the Sp8 gene gives a striking phenotype, with severe truncation of both forelimbs and hindlimbs, absent tail, as well as defects in anterior and posterior neuropore closure leading to exencephaly and spina bifida. Outgrowth of the limb depends on formation of the AER, a signaling center that forms at the limb bud apex. In Sp8 mutants, the AER precursor cells are induced and initially express multiple appropriate marker genes, but expression of these genes is not maintained and progression to a mature AER is blocked. These observations indicate that Sp8 functions downstream of Wnt3, Fgf10, and Bmpr1a in the signaling cascade that mediates AER formation.

Amino Acid Sequence↗
PubMed2003

Homotopic glial regulation of striatal projection neuron differentiation.

We have studied the differentiation of striatal projection neurons in co-culture with expanded glia from different regions of the embryonic mouse telencephalon. Our results show that when striatal progenitors are cultured on glia derived from the same region as they originate (i.e. the lateral ganglionic eminence), the neurons formed exhibit long processes. This is not the case when the cells are co-cultured with glia derived from the adjacent telencephalic region, the medial ganglionic eminence. Moreover, expression of the striatal projection neuron marker, dopamine- and cAMP-regulated phosphoprotein (DARPP-32) was significantly enhanced in neurons cultured on the homotopic glia. Thus, glial cultures derived from the lateral ganglionic eminence positively regulate the differentiation of striatal projection neurons in vitro.

Animals↗
PubMed2003

Identification of two distinct progenitor populations in the lateral ganglionic eminence: implications for striatal and olfactory bulb neurogenesis.

The lateral ganglionic eminence (LGE) is known to give rise to striatal projection neurons as well as interneurons, which migrate in the rostral migratory stream (RMS) to populate the granule cell and glomerular layers of the olfactory bulb. Because all of these neuronal subtypes express Distalless-related (DLX) homeobox proteins during their differentiation, we set out to further characterize progenitors in the Dlx-positive domain of the LGE. Previous studies have shown that the LIM homeobox protein Islet1 (ISL1) marks the LGE subventricular zone (SVZ) and differentiating striatal projection neurons. However, ISL1 is not expressed in neurons of the developing olfactory bulb or the RMS. We show here that the dorsal-most portion of the Dlx-expressing region of the LGE SVZ lacks ISL1 cells. This dorsal domain, however, contains cells that express the ETS transcription factor Er81, which is also expressed in granule and periglomerular cells of the developing and adult olfactory bulb. Moreover, the adult SVZ and RMS contain numerous Er81-positive cells. Fate-mapping studies using Dlx5/6-cre transgenic mice demonstrate that Er81-positive cells in the granule cell and glomerular layers of the olfactory bulb derive from the Dlx-expressing SVZ region. These findings suggest that the LGE SVZ contains two distinct progenitor populations: a DLX(+);ISL1(+) population representing striatal progenitors and a DLX(+);Er81(+) population comprising olfactory bulb interneuron progenitors. In support of this, mice mutant for the homeobox genes Gsh2 and Gsh1/2, which show olfactory bulb defects, exhibit dramatically reduced numbers of Er81-positive cells in the LGE SVZ as well as in the olfactory bulb mantle.

Animals↗
PubMed2003

Signaling to and from radial glia.

Radial glia represent the major glial cell type in the developing CNS and perform many essential functions, which range from acting as neural precursors to providing physical substrates for newborn neurons to migrate on. Previous work has shown that cell-cell signaling is important for the development of the radial glial phenotype. In particular, signals from newborn neurons appear to contribute significantly to the formation of this cell type. In addition, radial glia may be involved in reciprocal signaling roles that contribute to regional patterning and differentiation in the developing CNS.

Animals↗
PubMed2003

Dorsal-ventral patterning in the mammalian telencephalon.

The telencephalon is the most diverse region of the brain with respect to both morphology and neuronal subtypes. This fact makes the task of unraveling the mechanisms underlying the development of this brain region rather daunting. Recent attempts to subdivide the embryonic telencephalon into distinct progenitor domains along the dorsal-ventral axis have provided an important framework on which to begin this process. These progenitor domains are defined by the restricted expression of transcriptional regulators and are proposed to give rise to specific subtypes of neurons. Work over recent years has provided important insights into the establishment and maintenance of these progenitor domains in the developing telencephalon.

Animals↗
PubMed2003

Tlx and Pax6 co-operate genetically to establish the pallio-subpallial boundary in the embryonic mouse telencephalon.

We have examined the role of Tlx, an orphan nuclear receptor, in dorsal-ventral patterning of the mouse telencephalon. Tlx is expressed broadly in the ventricular zone, with the exception of the dorsomedial and ventromedial regions. The expression spans the pallio-subpallial boundary, which separates the dorsal (i.e. pallium) and ventral (i.e. subpallium) telencephalon. Despite being expressed on both sides of the pallio-subpallial boundary, Tlx homozygous mutants display alterations in the development of this boundary. These alterations include a dorsal shift in the expression limits of certain genes that abut at the pallio-subpallial boundary as well as the abnormal formation of the radial glial palisade that normally marks this boundary. The Tlx mutant phenotype is similar to, but less severe than, that seen in Small eye (i.e. Pax6) mutants. Interestingly, removal of one allele of Pax6 on the homozygous Tlx mutant background significantly worsens the phenotype. Thus Tlx and Pax6 cooperate genetically to regulate the establishment of the pallio-subpallial boundary. The patterning defects in the Tlx mutant telencephalon result in a loss of region-specific gene expression in the ventral-most pallial region. This correlates well with the malformation of the lateral and basolateral amygdala in Tlx mutants, both of which have been suggested to derive from ventral portions of the pallium.

Amygdala↗
PubMed2002

Regional specification of neurosphere cultures derived from subregions of the embryonic telencephalon.

We have studied the molecular specification of precursor cells in expanded neurosphere cultures derived from distinct subregions of the embryonic mouse telencephalon. These regionally derived cultures exhibited differential responses to the mitogens EGF and bFGF, suggesting that the precursors in these cultures were differentially specified as is the case in situ. To examine this further, cultures from each of the telencephalic subregions were expanded in both EGF and bFGF before differentiation. The neurons produced displayed molecular phenotypes similar to those normally derived from each of these regions in vivo. Moreover, analysis of gene expression in the undifferentiated cultures showed that the regionally derived neurospheres express many of the same developmental control genes as their in vivo counterparts. Taken together, the present findings suggest that precursor cells in neurosphere cultures, derived from distinct subregions of the embryonic telencephalon, maintain at least certain aspects of their molecular specification, even after significant expansion in vitro.

Animals↗
PubMed2002

Radial glia: multi-purpose cells for vertebrate brain development.

Radial glia are specialized cells in the developing nervous system of all vertebrates, and are characterized by long radial processes. These processes facilitate the best known function of radial glia: guiding the radial migration of newborn neurons from the ventricular zone to the mantle regions. Recent data indicate further important roles for these cells as ubiquitous precursors that generate neurons and glia, and as key elements in patterning and region-specific differentiation of the CNS. Thus, from being regarded mainly as support cells, radial glia have emerged as multi-purpose cells involved in most aspects of brain development.

Animals↗
PubMed2002

Event-related potential measures of the inhibition of information processing: I. Selective attention in the waking state.

This article reviews the effects of selective attention on event-related potentials (ERPs). Attention has little, if any, effect on short-latency exogenous ERPs. The longer-latency ERPs can be markedly affected by manipulation of the subject's level of attention. For example, a late positive wave, P300, appears to occur only if subjects actively detect an infrequently occurring target stimulus. However, a number of other late positive waves may also occur independently of the direction of attention, particularly if elicited by highly biologically or psychologically relevant stimuli. Attention may also interact with an earlier, apparently exogenous, negative waveform, N1. This could be due to the overlapping and summating effect of an attentional-related waveform, the processing negativity. The presentation of a physically deviant stimulus occurring among a train of homogeneous standard stimuli will elicit another negative wave, the mismatch negativity (MMN). The MMN has traditionally been thought to occur independently of attention. More recent studies have, however, shown that attention can modulate the MMN. This may, however, be explained by the summating effects of other overlapping components. Interpreting the scalp-recorded ERP can therefore require judicious care. Design of experiments must take into account the fact that the magnitude of attentional effects will depend on a number of different influences, some of which are very subtle and complex. A problem with any study in the waking and alert human is that the subject may not be able to completely ignore stimuli, in spite of instructions to do so. For this reason, the study of unconscious states, such as sleep, may prove to be especially fruitful in understanding the effects of attention in the waking state.

Animals↗