Population-Specific Regulation of Chmp2b by Lbx1 during Onset of Synaptogenesis in Lateral Association Interneurons (original) (raw)
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Neuron, 2002
neuronal progenitor cells possess regional identities, 2 Department of Neuroscience and distinct progenitor populations generate the differ-Max-Delbrü ck-Center for Molecular Medicine ent neuronal subtypes. In general, the dorsal part of the Robert Rö ssle Str. 10 spinal cord gives rise to neurons that process and relay 13122 Berlin sensory information, whereas the ventral part generates Germany the motoneurons and interneurons that coordinate mo-3 Howard Hughes Medical Institute tor output. Some principal events that control the speci-Department of Biochemistry and Molecular fication of various neuronal subtypes in the spinal cord Biophysics have been defined in recent studies (for recent reviews Columbia University see Lee and Jessell, 1999, 2000; Briscoe and Ericson, 701 West 168 th Street 2001). New York, New York 10032 A graded Shh signal and retinoic acid control the spatially organized development of ventral neuronal types. These signals direct the expression of patterning genes Summary to restricted subsets of progenitors along the ventral to dorsal axis (Lee and Jessell, 1999; Jessell, 2000; Briscoe Dorsal horn neurons in the spinal cord integrate and and Ericson, 2001). Expression of these patterning relay sensory information. Here, we show that the exgenes defines five ventral progenitor domains from pression of the homeobox gene Lbx1 distinguishes which motoneurons and V0-V3 interneurons arise. Altwo major neuronal classes generated in the dorsal though the expression of most patterning genes is extinspinal cord. The Lbx1 Ϫ (class A) and Lbx1 ؉ (class B) guished in postmitotic neurons, they instruct the postmineurons differ in their dependence on roof plate BMP totic neurons to express distinct homeodomain factors. signals for specification and settle in the deep and In this manner, patterning genes specify the neuronal superficial dorsal horn, respectively. Lbx1 misexpressubtypes that emerge from individual progenitor dosion blocks the differentiation of class A neurons. Conmains (Briscoe et al., 1999; Sander et al., 2000; Vallstedt versely, in Lbx1 mutant mice, class B neurons assume et al., 2001; Pierani et al., 2001). Homeodomain factors the identity of class A neurons. As a consequence, the such as HB9 and Evx1, which appear first in postmitotic morphology and neuronal circuitry of the dorsal horn neurons, determine or consolidate the final program of are aberrant. We conclude that Lbx1 distinguishes two neuronal differentiation (Arber et al., 1999; Thaler et al., major neuronal classes in the dorsal spinal cord and 1999; Moran-Rivard et al., 2001). is an important determinant of their distinct differenti-In the dorsal portion of the spinal cord, progenitor ation programs. cells are also patterned by extrinsic signals (Liem et al., 1997). These dorsal signals establish progenitor domains that express the bHLH factor genes Math1, Introduction Ngn1/2, and Mash1 (Lee et al., 1998; Ma et al., 1997; Gowan et al., 2001). Progenitors specified by dorsal sig-The dorsal horn of the spinal cord is the first central relay nals give rise to three dorsal neuronal subtypes, dI1-dI3 station for somatosensory perception. Interneurons and (see Results for the revised nomenclature of dorsal spiprojection neurons in the dorsal horn integrate incoming nal cord neurons used here), which are marked by sensory information and transmit this information to Lh2a/b, Lim1/2/Brn3a, and Isl1/2, respectively (Lee and higher brain centers (reviewed in Gillespie and Walker, Jessell, 1999; Gowan et al., 2001). Members of the BMP 2001; Julius and Basbaum, 2001). The assembly of these family are expressed in or near the roof plate at the time complex neuronal circuits depends on the generation dorsal progenitor domains are established and specify of functionally distinct types of dorsal horn neurons. dorsal neuronal subtypes. In explant culture, dI1 and Physiological studies have defined many distinct popu-dI3 neurons are specified by high and low BMP concenlations of dorsal horn neurons, which (1) process sentrations, respectively (Liem et al., 1997). Mutation of sory information associated with touch, pain, and heat GDF7, which encodes a BMP family member, prevents perceptions; (2) modulate reflex-specific motoneuron the emergence of late dI1 neurons (Lee et al., 1998). The output; and (3) relay sensory afferent information to the roof plate does not develop correctly in mice mutant for brainstem and the thalamus. Neurons with different the homeobox gene Lmx1a, which reduces the number physiological properties are segregated in distinct lamiof dI1 neurons (Millonig et al., 2000). In mice that express nae of the dorsal horn (Rexed, 1952; Brown, 1981). The diphtheria toxin A under the control of the GDF7 locus (GDF-DTA allele), the roof plate is eliminated, which interferes with the specification of dorsal progenitor do-4 Correspondence: cbirch@mdc-berlin.de 5 These authors contributed equally to this work. mains and blocks the generation of dI1 and dI3 neurons
Neuron, 1999
et al., 1997), Nkx2.2 (Briscoe et al., 1999), and members † Laboratory of Immunoregulation of the Gli family (Hui et al., 1994). Specifically, Nkx2.2 ϩ National Institute of Allergy progenitors appear to produce dorsal exiting MNs (d-MNs) and Infectious Diseases and a class of ventral interneurons (V3), whereas Pax6 ϩ National Institutes of Health progenitors give rise to ventral projecting MNs (v-MNs) Bethesda, Maryland 20892 and a number of distinct interneuron types (V1, V2) (Ericson et al., 1997; Sharma et al., 1998). In an analogous fashion, the dorsal neural tube is patterned by tumor Summary growth factor  (TGF) family molecules, including the bone morphogenetic proteins (BMPs) and activin, that Sonic hedgehog (Shh) specifies the identity of both initiate the specification of dorsal neuronal classes (Lee motor neurons (MNs) and interneurons with morphoet al., 1998). gen-like activity. Here, we present evidence that the Many of the transcription factors marking MN and homeodomain factor HB9 is critical for distinguishing interneuron classes have been suspected to control cell MN and interneuron identity in the mouse. Presumpfate specification, yet most are encountered in multiple tive MN progenitors and postmitotic MNs express cell types, including both interneurons and MNs (Tanabe HB9, whereas interneurons never express this factor. and Jessell, 1996; Pfaff and Kintner, 1998). For example, This pattern resembles a composite of the avian hothe LIM-HD factors Lhx3/4, known to promote the v-MN mologs MNR2 and HB9. In mice lacking Hb9, the gecell fate, are present in precursors for both v-MNs and netic profile of MNs is significantly altered, particularly V2 interneurons (Sharma et al., 1998) and can drive exby upregulation of Chx10, a gene normally restricted pression of the V2 gene Chx10 in ectopic contexts (Tanto a class of ventral interneurons. This aberrant gene abe et al., 1998). Thus, it is unclear how an MN utilizes expression is accompanied by topological disorganithese factors to establish its identity while avoiding the zation of motor columns, loss of the phrenic and abduinterneuron characteristics they might confer. More gencens nerves, and intercostal nerve pathfinding defects.
…, 2012
BMP activity is essential for many steps of neural development, including the initial role in neural induction and the control of progenitor identities along the dorsal-ventral axis of the neural tube. Taking advantage of chick in ovo electroporation, we show a novel role for BMP7 at the time of neurogenesis initiation in the spinal cord. Using in vivo loss-of-function experiments, we show that BMP7 activity is required for the generation of three discrete subpopulations of dorsal interneurons: dI1-dI3-dI5. Analysis of the BMP7 mouse mutant shows the conservation of this activity in mammals. Furthermore, this BMP7 activity appears to be mediated by the canonical Smad pathway, as we demonstrate that Smad1 and Smad5 activities are similarly required for the generation of dI1-dI3-dI5. Moreover, we show that this role is independent of the patterned expression of progenitor proteins in the dorsal spinal cord, but depends on the BMP/Smad regulation of specific proneural proteins, thus narrowing this BMP7 activity to the time of neurogenesis. Together, these data establish a novel role for BMP7 in primary neurogenesis, the process by which a neural progenitor exits the cell cycle and enters the terminal differentiation pathway.
Journal of Molecular Neuroscience, 1997
Homeodomain-containing genes of the Dlx family are expressed in the developing basal ganglia. To investigate the role of Dlx genes during development, we studied their cellular localization in primary cultures of embryonic basal telencephalon, and examined the changes in cellular phenotypes resulting from blockade of Dlx-2 expression. Cells containing Dlx-1, Dlx-2, and Dlx-5 mRNAs are immature cells of the neuronal lineage expressing the microtubule-associated proteins (MAPs) MAPIB and MAP2, but not glial fibrillary acidic protein (GFAP). Treatment of these cells with antisense oligonucleotides targeted to Dlx-2 caused a specific decrease of Dlx-2 mRNA and protein. This decrease in the Dlx-2 gene product was associated with a decrease in the expression of MAP2, a protein localized in neuronal dendrites, along with a smaller decrease in the 200-kDa neurofilament subunit (NF-H). Proteins expressed preferentially in axons were unchanged. This reduction in MAP2 expression was associated with a decrease in dendrite outgrowth and an increased level of celt proliferation. None of these changes were elicited by antisense oligonucleotides targeted to Dlx-1. We suggest that the Dlx-2 gene product regulates two interrelated aspects of neuronal differentiation: the exit from the mitotic cycle and the capability to grow MAP2-positive dendrites. As such, this gene product may be important for the establishment of neuronal polarity, setting the stage for afferent synaptic connectivity.
Vsx1 and Chx10 paralogs sequentially secure V2 interneuron identity during spinal cord development
Cellular and Molecular Life Sciences, 2019
Paralog factors are usually described as consolidating biological systems by displaying redundant functionality in the same cells. Here, we report that paralogs can also cooperate in distinct cell populations at successive stages of differentiation. In mouse embryonic spinal cord, motor neurons and V2 interneurons differentiate from adjacent progenitor domains that share identical developmental determinants. Therefore, additional strategies secure respective cell fate. In particular, Hb9 promotes motor neuron identity while inhibiting V2 differentiation, whereas Chx10 stimulates V2a differentiation while repressing motor neuron fate. However, Chx10 is not present at the onset of V2 differentiation and in other V2 populations. In the present study, we show that Vsx1, the single paralog of Chx10, which is produced earlier than Chx10 in V2 precursors, can inhibit motor neuron differentiation and promote V2 interneuron production. However, the single absence of Vsx1 does not impact on V2 fate consolidation, suggesting that lack of Vsx1 may be compensated by other factors. Nevertheless, Vsx1 cooperates with Chx10 to prevent motor neuron differentiation in early V2 precursors although these two paralog factors are not produced in the same cells. Hence, this study uncovers an original situation, namely labor division, wherein paralog genes cooperate at successive steps of neuronal development.
PLoS Biology, 2007
The mechanisms that regulate how dendrites target different neurons to establish connections with specific cell types remain largely unknown. In particular, the formation of cell-type-specific connectivity during postnatal neurogenesis could be either determined by the local environment of the mature neuronal circuit or by cell-autonomous properties of the immature neurons, already determined by their precursors. Using retroviral fate mapping, we studied the lamina-specific dendritic targeting of one neuronal type as defined by its morphology and intrinsic somatic electrical properties in neonatal and adult neurogenesis. Fate mapping revealed the existence of two separate populations of neuronal precursors that gave rise to the same neuronal type with two distinct patterns of dendritic targetinginnervating either a deep or superficial lamina, where they connect to different types of principal neurons. Furthermore, heterochronic and heterotopic transplantation demonstrated that these precursors were largely restricted to generate neurons with a predetermined pattern of dendritic targeting that was independent of the host environment. Our results demonstrate that, at least in the neonatal and adult mammalian brain, the pattern of dendritic targeting of a given neuron is a cell-autonomous property of their precursors.
Mechanisms of Development, 2005
The divergent homeobox-containing transcription factor, Tlx-3 (also known as Hox11L2/Rnx), is required for proper formation of firstorder relay sensory neurons in the developing vertebrate brainstem. To date, however, the inductive signals and transcriptional regulatory cascade underlying their development are poorly understood. We previously isolated the chick Tlx-3 homologue and showed it is expressed early (i.e. beginning at HH15) in distinct subcomponents of both the trigeminal/solitary and vestibular nuclei. Here we show via in vivo rhombomere inversions that expression of Tlx-3 is under control of local environmental signals. Our RNA in situ analysis shows expression of the BMP-specific receptor, Bmpr-1b, correlates well with Tlx-3. Furthermore, manipulation of the BMP signaling pathway in vivo via electroporation of expression vectors encoding either BMP or NOGGIN coupled with MASH1 gain-of-function experiments demonstrate that a BMP-mediated transcriptional cascade involving Cash1 and Tlx-3 specifies first-order relay sensory neurons in the developing brainstem. Notably, high-level Noggin misexpression results in an increase in newly differentiated Tlx-3 C neurons that correlates with a corresponding increase in the number of Calretinin C neurons in vestibular nuclei at later developmental stages strongly suggesting that Tlx-3, in addition to being required for proper formation of somatic as well as visceral sensory neurons in the trigeminal and solitary nuclei, respectively, is sufficient for proper formation of special somatic sensory neurons in vestibular nuclei. q
Genes & development, 2014
A complex array of genetic factors regulates neuronal dendrite morphology. Epigenetic regulation of gene expression represents a plausible mechanism to control pathways responsible for specific dendritic arbor shapes. By studying the Drosophila dendritic arborization (da) neurons, we discovered a role of the double-bromodomain and extraterminal (BET) family proteins in regulating dendrite arbor complexity. A loss-of-function mutation in the single Drosophila BET protein encoded by female sterile 1 homeotic [fs(1)h] causes loss of fine, terminal dendritic branches. Moreover, fs(1)h is necessary for the induction of branching caused by a previously identified transcription factor, Cut (Ct), which regulates subtype-specific dendrite morphology. Finally, disrupting fs(1)h function impairs the mechanosensory response of class III da sensory neurons without compromising the expression of the ion channel NompC, which mediates the mechanosensitive response. Thus, our results identify a nove...