Dlx-2 homeobox gene controls neuronal differentiation in primary cultures of developing basal ganglia (original) (raw)
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Dlx transcription factors regulate differentiation of dopaminergic neurons of the ventral thalamus
Molecular and Cellular Neuroscience, 2003
Recent studies have provided many lines of evidence that specific homeodomain factors act to regulate differentiation into specific neuron types. However, these studies have mainly focused on the caudal CNS, while in the forebrain, the regulation of neuron specification remains relatively unknown. To investigate the genetic regulatory networks that control neuron differentiation in the forebrain, we have analyzed the expression patterns and functions of DLX homeodomain factors in the ventral thalamus of early mouse embryos. During initial neurogenesis (E9.5-E10.5), DLX ϩ cells are the first progenitors to make terminal divisions and differentiate as neurons. We have defined a set of regulatory genes coexpressed with DLX, in both progenitors (PAX6 and MASH1) and in the differentiating neurons (PAX6, along with a combination of LIM-type homeodomain factors, including ISL1, Lhx1/Lim1, and Lhx5/Lim2). These initial neurons express tyrosine hydroxylase (TH), and become the PAX6-expressing A13 dopaminergic neurons of the zona incerta. To test for DLX function, the initial differentiation of the ventral thalamic neurons was examined in embryos mutant for Dlx1 and Dlx2. Dlx1/2 double homozygous mutants formed ventral thalamic neurons, but these neurons lacked PAX6, ISL1, and TH expression. These data suggest that DLX genes act as forebrain-specific factors linking general neuron-inducing signals to region-specific neuron differentiation programs.
Homeobox Gene Six3 is Required for the Differentiation of D2-Type Medium Spiny Neurons
Neuroscience Bulletin, 2021
Medium spiny neurons (MSNs) in the striatum, which can be divided into D1 and D2 MSNs, originate from the lateral ganglionic eminence (LGE). Previously, we reported that Six3 is a downstream target of Sp8/Sp9 in the transcriptional regulatory cascade of D2 MSN development and that conditionally knocking out Six3 leads to a severe loss of D2 MSNs. Here, we showed that Six3 mainly functions in D2 MSN precursor cells and gradually loses its function as D2 MSNs mature. Conditional deletion of Six3 had little effect on cell proliferation but blocked the differentiation of D2 MSN precursor cells. In addition, conditional overexpression of Six3 promoted the differentiation of precursor cells in the LGE. We measured an increase of apoptosis in the postnatal striatum of conditional Six3-knockout mice. This suggests that, in the absence of Six3, abnormally differentiated D2 MSNs are eliminated by programmed cell death. These results further identify Six3 as an important regulatory element dur...
Journal of Neuroscience Research, 2002
Several lines of evidence have indicated that changes in the structure of neuronal cytoskeleton provide the support for the dramatic morphological changes that occur during neuronal differentiation. It has been proposed that microtubule-associated proteins can contribute to the development of this phenomenon by controlling the dynamic properties of microtubules. In this report we have characterized the effect of the combined suppression of MAP1B and tau, and MAP1B and MAP2 on neuronal polarization in cultured hippocampal cells grown on a laminin-containing substrate. We have taken advantage of the use of a mouse line deficient in MAP1B expression obtained by the gene trapping approach. In addition to this engineered mice line we used the antisense oligonucleotide approach to induce the suppression of tau or MAP2, in wild type and MAP1B-deficient neurons. Together these results show a synergistic role for MAP1B/ MAP2 and MAP1B/TAU.
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
Molecular and Genetic Approaches to Defining Development of Neuronal Phenotypes
Neural development is dictated by hierarchal activation of a series of transcription factors that regulate the pattern of gene expression dictating neuronal phenotypes. We and others have identified a large family of transcription factors expressed in discrete temporal and spatial patterns during neuronal development , often in correlation with the appearance of specific cell types. By using a selection strategy, consensus DNA binding sites have been identified for several members of this family of transcription factors, and the ability of these proteins to activate specific neuronal transcription units has been established. Finally, analysis of mice deficient for a specific member of this family links these transcription factors to the processes of proliferation and commitment. Analysis of the genes encoding these developmental regulators suggests one mechanism by which memory of commitment might be maintained in mature neurons. Identification of Novel POD-Domain Gene Expression in Neural and Endocrine Development Using a strategy based on structural conservation of the POU domain, four new members of the POU-domain gene family were identified (10). Three clones were isolated from brain eDNA: Brn-1 and Brn-2 from human, and Brn-3 from rat. Tst-1 was isolated from rat testes eDNA Structural comparisons of the four new POD-domain proteins revealed that they were all highly related to Pit-1, Oct-1, Oct-2, and unc-86. Based on similarities, the eight known POU-domain proteins appar
PLoS ONE, 2012
Chmp2b is closely related to Vps2, a key component of the yeast protein complex that creates the intralumenal vesicles of multivesicular bodies. Dominant negative mutations in Chmp2b cause autophagosome accumulation and neurodegenerative disease. Loss of Chmp2b causes failure of dendritic spine maturation in cultured neurons. The homeobox gene Lbx1 plays an essential role in specifying postmitotic dorsal interneuron populations during late pattern formation in the neural tube. We have discovered that Chmp2b is one of the most highly regulated cell-autonomous targets of Lbx1 in the embryonic mouse neural tube. Chmp2b was expressed and depended on Lbx1 in only two of the five nascent, Lbx1expressing, postmitotic, dorsal interneuron populations. It was also expressed in neural tube cell populations that lacked Lbx1 protein. The observed population-specific expression of Chmp2b indicated that only certain population-specific combinations of sequence specific transcription factors allow Chmp2b expression. The cell populations that expressed Chmp2b corresponded, in time and location, to neurons that make the first synapses of the spinal cord. Chmp2b protein was transported into neurites within the motor-and association-neuropils, where the first synapses are known to form between E11.5 and E12.5 in mouse neural tubes. Selective, developmentally-specified gene expression of Chmp2b may therefore be used to endow particular neuronal populations with the ability to mature dendritic spines. Such a mechanism could explain how mammalian embryos reproducibly establish the disynaptic cutaneous reflex only between particular cell populations.