Biomedical subjects

Zhou-Feng Chen

Publications and source records attributed to Zhou-Feng Chen.

15 recordsLinked to original sources

PubMed2006

Recent advances in basic neurosciences and brain disease: from synapses to behavior.

Understanding basic neuronal mechanisms hold the hope for future treatment of brain disease. The 1st international conference on synapse, memory, drug addiction and pain was held in beautiful downtown Toronto, Canada on August 21-23, 2006. Unlike other traditional conferences, this new meeting focused on three major aims: (1) to promote new and cutting edge research in neuroscience; (2) to encourage international information exchange and scientific collaborations; and (3) to provide a platform for active scientists to discuss new findings. Up to 64 investigators presented their recent discoveries, from basic synaptic mechanisms to genes related to human brain disease. This meeting was in part sponsored by Molecular Pain, together with University of Toronto (Faculty of Medicine, Department of Physiology as well as Center for the Study of Pain). Our goal for this meeting is to promote future active scientific collaborations and improve human health through fundamental basic neuroscience researches. The second international meeting on Neurons and Brain Disease will be held in Toronto (August 29-31, 2007).

Behavior↗

PubMed2006

Lmx1b is essential for Fgf8 and Wnt1 expression in the isthmic organizer during tectum and cerebellum development in mice.

Secreted factors FGF8 and WNT1 are essential either for the inductive activity of the isthmus organizer or for the regionalization of the midbrain-hindbrain boundary (MHB). However, transcriptional regulation of these secreted factors during development remains to be elucidated. Here we show that the LIM homeobox gene Lmx1b is expressed in the anterior embryo as early as E7.5 and its expression becomes progressively restricted to the isthmus at E9.0. Analysis of gene expression in the MHB of the mutant embryos showed that many genes were lost by E9.5. In the MHB of Lmx1b-/- embryos, the expression of Fgf8, which normally occurs at the 4-somite stage, was completely absent, whereas Wnt1 was downregulated before the 4-somite stage. Moreover, transcription factors En1 and Pax2 were also downregulated prior to the 4-somite stage, whereas Gbx2 downregulation occurred at the 4-somite stage. By contrast, Otx2 and Pax6 expression was not affected in Lmx1b-/- embryos. The requirement of specific Lmx1b expression in the MHB was further confirmed by Wnt1-Cre-mediated region-specific conditional knockout of Lmx1b. As a result of these molecular defects, the development of the tectum and cerebellum was severely impaired in Lmx1b-/- mice. Taken together, our results indicate that Lmx1b plays an essential role in the development of the tectum and cerebellum by regulating expression of Fgf8, Wnt1 and several isthmus-related transcription factors in the MHB, and is a crucial component of a cross-regulatory network required for the induction activity of the isthmic organizer in the MHB.

Animals↗

PubMed2006

Lmx1b is required for maintenance of central serotonergic neurons and mice lacking central serotonergic system exhibit normal locomotor activity.

Central serotonergic neurons have been implicated in numerous animal behaviors and psychiatric disorders, but the molecular mechanisms underlying their development are not well understood. Here we generated Lmx1b (LIM homeobox transcription factor 1 beta) conditional knock-out mice (Lmx1b(f/f/p)) in which Lmx1b was only deleted in Pet1 (pheochromocytoma 12 ETS factor-1)-expressing 5-HT neurons. In Lmx1b(f/f/p) mice, the initial generation of central 5-HT neurons appeared normal. However, the expression of both 5-HT-specific and non-5-HT-specific markers was lost in these neurons at later stages of development. The loss of gene expression is concomitant with downregulation of Lmx1b expression, with the exception of serotonin transporter Sert and tryptophan hydroxylase TPH2, whose expression appears to be most sensitive to Lmx1b. Interestingly, the expression of Pet1 is tightly coupled with expression of Lmx1b during later stages of embryonic development, indicating that Lmx1b maintains Pet1 expression. In Lmx1b(f/f/p) mice, almost all central 5-HT neurons failed to survive. Surprisingly, Lmx1b(f/f/p) mice survived to adulthood and exhibited normal locomotor activity. These data reveal a critical role of Lmx1b in maintaining the differentiated status of 5-HT neurons. Lmx1b(f/f/p) mice with normal locomotor function should provide a unique animal model for examining the roles of central 5-HT in a variety of animal behaviors.

Animals↗

PubMed2006

Involvement of DRG11 in the development of the primary afferent nociceptive system.

During development, dorsal root ganglia (DRG) neurons differentiate in various subpopulations, nociceptive neurons belonging in the small-diameter class. This study addresses the role played by DRG11, a transcription factor expressed in the spinal area of projection of small-diameter DRG neurons, in the development of the primary afferent system. The various subclasses of DRG neurons were compared between wild-type and Drg11(-/-) mice at embryonic and postnatal life. In Drg11(-/-) mice, numbers of small peptidergic and non-peptidergic DRG neurons were decreased at P7 concomitant with abnormal cell death. Innervation by small DRG neurons was impaired in cutaneous, visceral and deep tissues. Large DRG neurons were not affected. The data point to a role for DRG11 in early postnatal survival of normally generated small primary afferent neurons innervating various kinds of peripheral tissues, which would explain the nociceptive deficits observed in Drg11-null mutant mice.

Animals↗

PubMed2006

Molecular mapping of developing dorsal horn-enriched genes by microarray and dorsal/ventral subtractive screening.

The dorsal horn of the spinal cord consists of distinct laminae that serve as a pivotal region for relaying a variety of somatosensory signals such as temperature, pain, and touch. The molecular mechanisms underlying the development of the dorsal horn are poorly understood. To define a molecular map of the dorsal horn circuit, we have profiled dorsal horn-enriched (DHE) gene expression in dorsal spinal cords on embryonic day 15.5 (E15.5) by genome-wide microarray and smart subtractive screening based on polymerase chain reaction (PCR). High-throughput in situ hybridization (ISH) was carried out to validate the expression of 379 genes in the developing dorsal spinal cord. A total of 113 DHE genes were identified, of which 59% show lamina-specific expression patterns. Most lamina-specific genes were expressed across at least two laminae, however. About 32% of all DHE genes are transcription factors, which represent the largest percentage of the group of all DHE functional classifications. Importantly, several individual lamina-specific transcription factors such c-Maf, Rora, and Satb1 are identified for the first time. Epistasis studies revealed several putative effectors of known DHE transcription factors such as Drg11, Tlx3(Rnx), and Lmx1b. These effector genes, including Grp, Trpc3, Pcp4, and Enc1, have been implicated in synaptic transmission, calcium homeostasis, and structural function and thus may have similar roles in the dorsal horn. The identification of a large number of DHE genes, especially those that are lamina specific, lays a foundation for future studies on the molecular machinery that controls the development of the dorsal horn and on functional differences of these distinct laminae in the dorsal spinal cord.

Animals↗

PubMed2006

Molecular determinants of the face map development in the trigeminal brainstem.

The perception of external sensory information by the brain requires highly ordered synaptic connectivity between peripheral sensory neurons and their targets in the central nervous system. Since the discovery of the whisker-related barrel patterns in the mouse cortex, the trigeminal system has become a favorite model for study of how its connectivity and somatotopic maps are established during development. The trigeminal brainstem nuclei are the first CNS regions where whisker-specific neural patterns are set up by the trigeminal afferents that innervate the whiskers. In particular, barrelette patterns in the principal sensory nucleus of the trigeminal nerve provide the template for similar patterns in the face representation areas of the thalamus and subsequently in the primary somatosensory cortex. Here, we describe and review studies of neurotrophins, multiple axon guidance molecules, transcription factors, and glutamate receptors during early development of trigeminal connections between the whiskers and the brainstem that lead to emergence of patterned face maps. Studies from our laboratories and others' showed that developing trigeminal ganglion cells and their axons depend on a variety of molecular signals that cooperatively direct them to proper peripheral and central targets and sculpt their synaptic terminal fields into patterns that replicate the organization of the whiskers on the muzzle. Similar mechanisms may also be used by trigeminothalamic and thalamocortical projections in establishing patterned neural modules upstream from the trigeminal brainstem.

Animals↗

PubMed2005

Upregulation of forebrain NMDA NR2B receptors contributes to behavioral sensitization after inflammation.

Transgenic overexpression of NMDA NR2B receptors in forebrain regions increased behavioral responses to persistent inflammatory pain. However, it is not known whether inflammation leads to the upregulation of NR2B receptors in these regions. Here, we show that peripheral inflammation increased the expression of NMDA NR2B receptors and NR2B receptor-mediated synaptic currents in the anterior cingulate cortex (ACC). In freely moving mice, the increase in NR2B receptors after inflammation contributed to enhanced NMDA receptor-mediated responses in the ACC. Inhibition of NR2B receptors in the ACC selectively reduced behavioral sensitization related to inflammation. Our results demonstrate that the upregulation of NR2B receptors in the ACC contributes to behavioral sensitization caused by inflammation.

Animals↗

PubMed2005

Ventral migration of early-born neurons requires Dcc and is essential for the projections of primary afferents in the spinal cord.

Neuronal migration and lamina-specific primary afferent projections are crucial for establishing spinal cord circuits, but the underlying mechanisms are poorly understood. Here, we report that in mice lacking Dcc (deleted in colorectal cancer), some early-born neurons could not migrate ventrally in the spinal cord. Conversely, forced expression of Dcc caused ventral migration and prevented dorsolateral migration of late-born spinal neurons. In the superficial layer of the spinal cord of Dcc-/- mutants, mislocalized neurons are followed by proprioceptive afferents, while their presence repels nociceptive afferents through Sema3a. Thus, our study has shown that Dcc is a key molecule required for ventral migration of early-born neurons, and that appropriate neuronal migration is a prerequisite for, and coupled to, normal projections of primary afferents in the developing spinal cord.

Animals↗

PubMed2005

Generation and characterization of the PKC gamma-Cre mouse line.

PKCgamma is a protein kinase C (PKC) isoform that is expressed in the central nervous system (CNS). We generated a PKCgamma-Cre mouse line and characterized the expression and activity of the Cre protein. Our studies show that Cre expression largely recapitulates the endogenous expression of PKCgamma. Several major sites of Cre expression are the cerebral cortex, hippocampus, thalamus, amygdala, and spinal cord. Examination of PKCgamma-Cre/ROSA26 mice reveals a similar X-gal staining pattern in the CNS, indicating that Cre recombinase is capable of removing LoxP sites in vivo. These data indicate that the PKCgamma-Cre mouse line could be a useful reagent for generating Cre-mediated tissue-specific knockouts in the CNS.

Animals↗

PubMed2005

A neurological phenotype in nail patella syndrome (NPS) patients illuminated by studies of murine Lmx1b expression.

Nail patella syndrome (NPS) is an autosomal dominant disorder affecting development of the limb, kidney and eye. NPS is the result of heterozygous loss-of-function mutations in the LIM-homeodomain transcription factor, LMX1B. Recent studies suggest that the NPS phenotype may be more extensive than recognized previously including neurologic and neurobehavioral aspects. To determine whether these findings correlated with the expression of Lmx1b during development, an internal ribosomal entry site-LacZ reporter was inserted into the 3'UTR of the endogenous murine gene. The pattern of Lmx1b expression during the development of the limb, eye and kidney correlates with the NPS phenotype. Additional sites of expression were observed in the central nervous system (CNS). The effects of the absence of Lmx1b in the CNS were determined in lmx1b-/- mice by histology and immunocytochemistry. Lmx1b is required for the differentiation and migration of neurons within the dorsal spinal cord. The inability of afferent sensory neurons to migrate into the dorsal horn is entirely consistent with diminished pain responses in NPS patients.

Animals↗

PubMed2004

Focal adhesion kinase in netrin-1 signaling.

Netrins are a family of secreted molecules that are important for axonal outgrowth and guidance in the developing nervous system. However, the signaling mechanisms that lie immediately downstream of netrin receptors remain poorly understood. Here we report that the netrin receptor DCC (deleted in colorectal cancer) interacts with the focal adhesion kinase (FAK), a kinase implicated in regulating cell adhesion and migration. FAK was expressed in developing brains and was localized with DCC in cultured neurons. Netrin-1 induced FAK and DCC tyrosine phosphorylation. Disruption of FAK signaling abolished netrin-1-induced neurite outgrowth and attractive growth cone turning. Taken together, these results indicate a new signaling mechanism for DCC, in which FAK is activated upon netrin-1 stimulation and mediates netrin-1 function; they also identify a critical role for FAK in axon navigation.

Animals↗

PubMed2004

Lmx1b controls the differentiation and migration of the superficial dorsal horn neurons of the spinal cord.

The differentiation and migration of superficial dorsal horn neurons and subsequent ingrowth of cutaneous afferents are crucial events in the formation of somatosensory circuitry in the dorsal spinal cord. We report that the differentiation and migration of the superficial dorsal horn neurons are regulated by the LIM homeobox gene Lmx1b, and its downstream targets Rnx and Drg11, two transcription factors implicated in the development of dorsal horn circuitry. An analysis of Lmx1b mutants shows that Lmx1b normally acts to maintain the expression of the Ebf genes and to repress the Zic genes. Lmx1b mutants also exhibit the disruption of the cutaneous afferent ingrowth, suggesting that the dorsal horn cells might provide important cues guiding sensory axons into the dorsal spinal cord. Our results thus indicate that Lmx1b has a pivotal role in genetic cascades that control the assembly of circuitry in the superficial dorsal horn.

Animals↗

PubMed2003

Formation of whisker-related principal sensory nucleus-based lemniscal pathway requires a paired homeodomain transcription factor, Drg11.

Little is known about the molecular mechanisms underlying the formation of the principal sensory nucleus (PrV) of the trigeminal nerve, a major relay station for somatotopic pattern formation in the trigeminal system. Here, we show that mice lacking Drg11, a homeodomain transcription factor, exhibit defects within the PrV, which include an aberrant distribution of Drg11-/- cells, altered expression of a molecular marker, unusual projections of primary afferents from trigeminal ganglion cells, and, subsequently, increased cell death. In addition, surviving PrV cells exhibit delayed and more spatially restricted ascending projections to the ventral posterior medial nucleus of the thalamus (VPm). These early embryonic abnormalities in the PrV lead to the failure to develop whisker-related patterns in the PrV, VPm, and somatosensory cortex. By contrast, somatotopic patterns exist in the spinal trigeminal subnuclei interpolaris (SpVi) and subnuclei caudalis (SpVc) and the dorsal column nucleus-based lemniscal and cortical pathway. Thus, the deficits in the trigeminal system of Drg11-/- mice are specific to the PrV. Our results demonstrate that Drg11 is essential for proper cellular differentiation and, subsequently, for the formation of the whisker-related lemniscal and cortical structures.

Afferent Pathways↗

PubMed2003

Lmx1b is essential for the development of serotonergic neurons.

The specification and differentiation of serotonergic (5-HT) neurons require both extrinsic signaling molecules and intrinsic transcription factors to work in concert or in cascade. Here we identify the genetic cascades that control the specification and differentiation of 5-HT neurons in mice. A major determinant in the cascades is an LIM homeodomain-containing gene, Lmx1b, which is required for the development of all 5-HT neurons in the central nervous system. Our results suggest that, during development of 5-HT neurons, Lmx1b is a critical intermediate factor that couples Nkx2-2-mediated early specification with Pet1-mediated terminal differentiation. Moreover, our data indicate that genetic cascades controlling the caudal and rostral 5-HT neurons are distinct, despite their shared components.

Animals↗

PubMed2002

1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system.

Inappropriate activation of the renin-angiotensin system, which plays a central role in the regulation of blood pressure, electrolyte, and volume homeostasis, may represent a major risk factor for hypertension, heart attack, and stroke. Mounting evidence from clinical studies has demonstrated an inverse relationship between circulating vitamin D levels and the blood pressure and/or plasma renin activity, but the mechanism is not understood. We show here that renin expression and plasma angiotensin II production were increased severalfold in vitamin D receptor-null (VDR-null) mice, leading to hypertension, cardiac hypertrophy, and increased water intake. However, the salt- and volume-sensing mechanisms that control renin synthesis are still intact in the mutant mice. In wild-type mice, inhibition of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] synthesis also led to an increase in renin expression, whereas 1,25(OH)(2)D(3) injection led to renin suppression. We found that vitamin D regulation of renin expression was independent of calcium metabolism and that 1,25(OH)(2)D(3) markedly suppressed renin transcription by a VDR-mediated mechanism in cell cultures. Hence, 1,25(OH)(2)D(3) is a novel negative endocrine regulator of the renin-angiotensin system. Its apparent critical role in electrolytes, volume, and blood pressure homeostasis suggests that vitamin D analogues could help prevent or ameliorate hypertension.

Angiotensin II↗