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Topical Review |
1 Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA
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Abstract |
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 Top Abstract IntroductionReferences |
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(Received 14 May 2006;
accepted after revision 3 July 2006;
first published online 6 July 2006)
Corresponding author Q. Ma: Dana-Farber Cancer Institute and Department of Neurobiology, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA. Email: qiufu_ma{at}dfci.harvard.edu
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Introduction |
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In the past two decades, several key principles regarding neuronal cell type specification have emerged. First, extrinsic signals pattern the neural tube spatially and temporally, such that distinct types of neurons are formed at defined places and times (McConnell, 1995; Jessell, 2000; Anderson, 2001; Livesey & Cepko, 2001; Kiecker & Lumsden, 2005; Guillemot et al. 2006). Second, transcription factors (TFs) often act in combination to control neuronal cell type specification – the so-called TF combinatorial control mode (Lee & Pfaff, 2001). In this article, I will discuss to what degree and how TFs are used to establish various aspects of neuronal identity.
Genome-scale analysis of TF expression in the mouse nervous system
The mammalian genome encodes about 1500 TFs that contain known DNA-binding motifs (Gray et al. 2004). Since completion of the sequencing of the human and mouse genomes, my colleagues and I have been using high throughput in situ hybridization to compile a genome-scale map of TF expression in the developing mouse nervous system. With 80% screen coverage, we have identified over 350 TFs that show spatially and/or temporally restricted expression (Gray et al. 2004).
Several conclusions can be drawn from this genome-scale analysis, as well as from numerous independent studies. First, a given TF is often expressed in multiple brain regions. In other words, TFs that are expressed exclusively in one type of neuron, such as the restriction of Pet1 to serotonergic neurons (Hendricks et al. 1999), are extremely rare. This characteristic of TF expression patterns is consistent with the current view that TFs act in combination to control cell type specification (or a TF may control a feature shared by different types of neurons). Second, TF expression is sufficient to define basic brain anatomy, such as lamina-specific organization in the neocortex, retina and cerebellum, and nuclear organization in the thalamus and hypothalamus (Kandel et al. 2000; Nakagawa & O'Leary, 2001; Blackshaw et al. 2004; Gray et al. 2004; Guillemot et al. 2006) and the gradient expression of many TFs in the striatum may underlie the genetic basis for a topographic organization in this brain area (Kandel et al. 2000; Gray et al. 2004). Third, within a brain region, TF expression is able to mark the major populations of neurons, such as the Purkinje versus granule cells in the cerebellum, or ganglion versus amacrine neurons in the retina. Furthermore, TF expression can at least partially reveal additional heterogeneity within a defined population of neurons. For example, many TF genes are expressed with differential density within retinal ganglion or amacrine cell layers (Blackshaw et al. 2004; Gray et al. 2004).
However, combinatorial TF expression alone might be insufficient to account for the entirety of nerve cell diversity. For example, within a given cerebellar compartment, no TF expression is able to mark Purkinje cell diversity that was revealed by restricted expression of protocadherin molecules in small fractions of these neurons (Gray et al. 2004; Esumi et al. 2005; D. Rowitch, personal communication). TF expression also appears unable to mark the reported diversity of the peripheral nociceptive sensory neurons (C. Cen & Q. Ma, unpublished data). The emerging theme is that while combinatorial TF expression is sufficient to define the basic framework of the nervous system, other control mechanisms probably contribute to the generation of cell diversity (see below).
Specification of generic neuronal identity
Each neuron shares a set of features, such as the expression of pan-neural markers, elaboration of dendritic and axonal processes, formation of synaptic connections, and the ability to generate and transduce electrical signals. Specification of these generic neuronal features (or initiation of the process leading to the establishment of these features) is controlled by a group of neuronal determination genes that encode basic-helix–loop-helix (bHLH) class TFs (Anderson et al. 1997; Lee, 1997; Schuurmans & Guillemot, 2002). Harold Weintraub and colleagues first established bHLH genes as master regulators in muscle cell fate determination (Weintraub, 1993). Genetic studies in Drosophila then showed that several bHLH genes, called proneural genes, determine a neural versus an epidermal cell fate (Jan & Jan, 1993). Subsequently, mammalian homologs of the fly proneural genes, including Mash1, Neurogenin1–3 (Ngn1–3), and Math1/3, serve as vertebrate neuronal determination genes (Anderson et al. 1997; Lee, 1997; Schuurmans & Guillemot, 2002).
An important feature of determination factors is their capacity to convert other types of cells into neurons. For example, Ngn1/2 and their downstream target NeuroD are able to drive multipotent neural precursors, ectodermal cells and even muscle precursors into ‘differentiated’ neurons (Lee et al. 1995; Ma et al. 1996; Perez et al. 1999; Sun et al. 2001). In the case of the muscle determination factor MyoD, the determination activity is conferred by its ability to bind and activate target genes at repressed chromatin states, thereby orchestrating a de novo muscle differentiation program (Gerber et al. 1997; Tapscott, 2005). Neuronal determination factors probably contain similar capacities, by recruiting chromatin-remodelling complexes and activating High Mobility Group (HMG) class TFs (Koyano-Nakagawa et al. 1999; Sun et al. 2001; Sandberg et al. 2005). However, to date surprisingly little has been shown about how the expression of neuronal determination genes leads to the eventual establishment of generic neuronal identity.
Neurogenesis coupled with neuronal cell type specification
Vertebrate neuronal determination genes are expressed in largely non-overlapping populations of neural precursors (Fig. 1) (Gradwohl et al. 1996; Sommer et al. 1996; Ma et al. 1997; Gowan et al. 2001; Helms & Johnson, 2003). One important consequence of this expression pattern is the coupling of neurogenesis with neuronal cell type specification (Anderson & Jan, 1997; Brunet & Ghysen, 1999; Bertrand et al. 2002; Helms & Johnson, 2003). Indeed, elegant genetic manipulations show that Ngn2 and Mash1 can replace each other in driving generic neuronal differentiation, but cannot do that in specifying neuronal subtypes (Parras et al. 2002).
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Specification of neurotransmitter phenotype
One of the best-studied neuronal features in the mammalian nervous system is the specification of neurotransmitter phenotypes. Interested readers are referred to several recent reviews and articles that describe the development of three major modulator neurotransmitters, including dopamine, serotonin and noradrenaline, as well as the establishment of cholinergic transmitter phenotype (Goridis & Rohrer, 2002; Spitzer et al. 2004; Howard, 2005; Thiel, 2006). In this article, I only discuss the specification of two principal excitatory and inhibitory transmitters, glutamate and GABA, which are established in a largely mutually exclusive manner in the vertebrate brain (Bennett & Balcar, 1999; Fremeau et al. 2004). A set of studies suggests that the choice of these two transmitter phenotypes is regulated at several levels.
First, neuronal determination genes are actively involved in determining transmitter phenotypes. As mentioned above, Ngn1/2 and Mash1 determine the glutamatergic versus the GABAergic cell fates in the forebrain and spinal cord spinal neurons (Fode et al. 2000; Schuurmans et al. 2004; Mizuguchi et al. 2006), and they also determine different types of monoaminergic neurons in the midbrain and the hindbrain (Hirsch et al. 1998; Goridis & Rohrer, 2002; Pattyn et al. 2004; Andersson et al. 2006a, b; Jeong et al. 2006; Kele et al. 2006). The involvement of neuronal determination genes explains why transmitter phenotype is among the earliest neuronal features established in differentiating neurons (Goridis & Rohrer, 2002). Part of the logic behind this early specification is the involvement of neurotransmitters in controlling a variety of neuronal differentiation processes (Vitalis & Parnavelas, 2003; Represa & Ben-Ari, 2005).
Second, there are binary genetic switches that operate in early post-mitotic neurons. In the dorsal spinal cord, three sets of post-mitotic TFs are involved in choosing an excitatory versus an inhibitory cell fate. First, the homeobox gene Lbx1 defines a basal GABAergic differentiation state (Cheng et al. 2005). Second, the homeobox genes Tlx1 and Tlx3 antagonize Lbx1 to promote a glutamatergic cell fate (Cheng et al. 2004, 2005). Finally, the bHLH gene Ptf1a acts to suppress Tlx3 expression, which in turns allows Lbx1 to promote GABAergic differentiation (Glasgow et al. 2005; Hoshino et al. 2005). Loss or gain of all these genes is sufficient to cause a cell fate switch, from glutamatergic to GABAergic or vice versa (Cheng et al. 2004,2005; Glasgow et al. 2005).
Third, neuronal activity can regulate excitatory and inhibitory transmitter phenotype in a homeostatic fashion (Spitzer et al. 2004). In the developing frog spinal cord, an increase in neuronal activity increases the number of neurons expressing inhibitory neurotransmitters, whereas a decrease in neuronal activity results in an exactly inverse result: more excitatory and fewer inhibitory neurons (Borodinsky et al. 2004). In the dentate gyrus of rat hippocampus, enhanced excitability under seizures can promote GABAergic transmitter phenotype development in presumably glutamatergic granule cells (Schwarzer & Sperk, 1995; Sloviter et al. 1996; Ramirez & Gutierrez, 2001; Gutierrez, 2003). It will be interesting to determine if neuronal activity acts to modulate the expression or function of those post-mitotic switch factors, such as Tlx3 and Lbx1.
It is noteworthy that the establishment of the excitatory and inhibitory transmitter phenotypes is controlled by a set of region-specific TFs, rather than through a unitary transcriptional program. For example, the Dlx class homeobox genes are implicated in specification of forebrain GABAergic neurons, but not in other brain areas (Anderson et al. 1999). The bHLH gene Heslike controls GABAergic differentiation in the midbrain (Miyoshi et al. 2004), whereas Tlx3, Lbx1 and Ptf1a operate in the cerebellum, the hindbrain and/or the spinal cord (Gross et al. 2002; Müller et al. 2002; Cheng et al. 2004; Glasgow et al. 2005; Hoshino et al. 2005). One advantage for the evolvement of these TFs is to couple the specification of generic transmitter phenotype with that of region-specific neuronal identity (Cheng et al. 2004; Guillemot et al. 2006), similar to the function of the neuronal determination genes.
Specification of neuronal morphology and other neuronal identity
The identity of a mature neuron includes a defined axonal trajectory pattern and a unique pattern of dendritic arborization. Many TFs have been shown to control axon pathfinding or pruning. For example, the lim-homeobox TFs and hox proteins control motor neuron innervation to specific muscle targets (Lee & Pfaff, 2001; Dasen et al. 2005), Fezl and Ctip2 control long-range descending projections of cortico-spinal motor neurons (Arlotta et al. 2005; Chen et al. 2005; Molyneaux et al. 2005), Tbx5, Vax2 and Islet2 determine topographic projections of retinal ganglion neurons (Schulte et al. 1999; Koshiba-Takeuchi et al. 2000; Mui et al. 2002; Pak et al. 2004), the runt-domain transcription factors (Runx1 and Runx3) and the Ets-domain protein (Er81) control central target selections by somatic sensory afferents (Arber et al. 2003; Chen et al. 2006a, b; Kramer et al. 2006), and the homeobox protein Otx1 controls axonal pruning (Weimann et al. 1999). In Drosophila, a recent genome-scale analysis has identified a large set of TFs that control dendritic morphogenesis (Parrish et al. 2006). However, in mammals only a few TFs that control dendritic morphology have been characterized (Aizawa et al. 2004; Gaudilliere et al. 2004; Cobos et al. 2005; Hand et al. 2005).
The function of a neuron also depends on appropriate expression of a variety of functional proteins, such as neurotransmitter receptors, and voltage-gated calcium, sodium and potassium channels. Surprisingly, to date only a few TFs that control the expression of these types of functional genes have been reported (Cheng et al. 2004, 2006b; Eng et al. 2004; Li et al. 2006). One notable exception is the extensive characterization of TFs that control the expression of a variety of hormone genes in the pituitary gland (Zhu et al. 2005). To promote this area of research, it is becoming critically important to compile a genome-scale map of the spatial and temporal distribution patterns of ion channels and receptors in the developing nervous system, and to correlate this map with the aforementioned TF map.
Coordinated regulation of neuronal identity
In principle, the various aspects of neuronal features could be independently regulated, in a piecemeal manner. Surprisingly, a number of studies suggest a considerable coordinated regulation of neuronal phenotype in a given neuron. For example, HB9/MNR2 coordinates motor neuron development, including the establishment of cholinergic transmitter phenotype and axonal trajectory patterns (Tanabe et al. 1998). Pet1 and Lmx1b regulate the expression of a set of genes that define the serotonergic transmitter phenotype, including the enzymes for serotonin (5-HT) synthesis and the transporters that package 5-HT to synaptic vesicles or re-uptake 5-HT after synaptic release (Cheng et al. 2003; Ding et al. 2003; Hendricks et al. 2003). Crx controls the expression of a large set of functional genes in photoreceptors (Furukawa et al. 1997). Phox2a and Phox2b specify distinct classes of neurons and features within the autonomic circuitry (Brunet & Pattyn, 2002; Thiel, 2006). Finally, our genome-scale TF screen so far only identified a few TFs that distinguish nociceptors from proprioceptors or mechanoceptors (C. Cen & Q. Ma, unpublished data). Indeed, one nociceptor-specific TF Runx1 is able to coordinate the expression of neurotrophin receptors, neuropetides, and two-dozen ion channels and receptors, as well as the establishment of specific afferent central target selections (Chen et al. 2006b; Kramer et al. 2006; Marmigere et al. 2006). These findings have practical implications as the coordinated control of neuronal phenotype by a small number of TFs has been exploited to drive embryonic stem cells to differentiate into defined neuronal cell types, including dopaminergic and motor neurons, thereby opening the door for future cell replacement therapy for certain neurological disorders (Kim et al. 2002; Wichterle et al. 2002; Andersson et al. 2006b).
Beyond TF combinatorial codes
One important principle emerging from studies over the past two-decades is that combinatorial TF codes are able to define the major populations of neuronal cells. This control mechanism emphasizes the precision in genetic control of nervous system development. However, previously unrecognized cellular complexity has been revealed in systems where neuronal morphology or functional genes have been extensively characterized. For example, over two dozen subtypes of retinal amacrine cells are distinguished by their unique morphology, and olfactory neurons show a monogenic expression of over 1000 odour receptors (Buck, 2000; Masland, 2004). This level of complexity raises the question about whether the spatial and temporal patterning has enough resolution to provide a combinatorial code of TFs (and cofactors) for individual neuronal subtypes. Indeed, increasing evidence suggests that cell diversity can arise from a population of neurons that might share the same TF (and cofactor) codes (Shykind, 2005). Here I only discuss a few of many possible mechanisms.
One is the involvement of the locus control region (LCR) that was first shown to control beta-globin gene expression (Li et al. 1999). In this model TFs that bind to LCR interact with only one of many target promoters clustered in the same chromosome (Fig. 2A). In the nervous system, this control mechanism has been proposed for a stochastic activation of either red or green cone pigment gene in a given photoreceptor (Smallwood et al. 2002), or the choice of one olfactory receptor (OR) from a cluster of OR genes (Serizawa et al. 2003). A variation of this control model is the involvement of a specific locus in the nucleus for the activation of a group of target genes, as recently demonstrated by the generation of monoallelic expression of variant surface glycoprotein genes in Trypanosoma brucei (Navarro & Gull, 2001).
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Third, cell diversity can be generated after axons reach distinct targets. For example, the sympathetic neurons that innervate the sweat gland make a switch in transmitter phenotypes, from noradrenergic to cholinergic (Francis & Landis, 1999). Similarly, the identity of postsynaptic neurons can be re-defined by distinct presynaptic inputs (Sur & Rubenstein, 2005). Target-derived signalling could change TF/cofactor codes, or modulate TF activity through post-translational modifications (Fig. 2C).
Finally, neuronal cell type specification is also subject to epigenetic control, through histone modifications, DNA methylation and the remodelling of chromatin architectures (Hsieh & Gage, 2005). While some TFs are capable of recruiting enzymatic cofactors to modify chromatin structures, other TFs only bind target promoters at open chromatin states (Maier et al. 2004). Therefore, cell diversity can emerge if a group of neurons inherit distinct chromatin states, even if they share the same TF codes (Fig. 2D). Recent years have also started to recognize the important roles of non-coding RNA, including microRNA and small interfering RNA (siRNA), in controlling gene expression at both chromatin and post-transcription levels, and these new regulatory molecules will most probably contribute to the generation of neuronal cell diversity (Mattick & Makunin, 2005).
Concluding remarks
Generation of nerve cell diversity is a complex process and involves multiple control mechanisms. At early stages of neural development, spatial and temporal patterning leads to the specification of distinct groups of precursors and neurons, each of which is often defined and controlled by a combinatorial expression of TFs. This deterministic control mechanism ensures that the framework of the nervous system is subject to precise ‘hardwired’ genetic control, a feature certainly critical for proper brain function. However, cell diversity can be generated through epigenetic or stochastic regulation of gene expression in a group of functionally related neurons that may share the same TF codes. These latter control mechanisms suggest the existence of an intrinsic variability in vertebrate nervous system development. In other words, individual difference may arise even before nurturing starts to reshape the brain.
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References |
|---|
|
TopAbstractIntroductionReferences |
|---|
Anderson DJ (2001). Stem cells and pattern formation in the nervous system: the possible versus the actual. Neuron 30, 19–35.[CrossRef][Medline]
Anderson
DJ, Groves
A, Lo
L, Ma
Q, Rao
M, Shah
NM
&
Sommer
L (1997). Cell lineage determination and the control of neuronal identity in the neural crest. Cold Spring Harb Symp Quant Biol
62, 493–504.
Anderson DJ & Jan YN (1997). The determination of the neuronal phenotype. In Molecular and Cellular Approaches to Neural Development, ed. Cowan WM, Jessell TM & Zipursky SL, pp. 26–63. Oxford University Press, New York.
Anderson
S, Mione
M, Yun
K
&
Rubenstein
JL (1999). Differential origins of neocortical projection and local circuit neurons: role of Dlx genes in neocortical interneuronogenesis. Cereb Cortex
9, 646–654.
Andersson
E, Jensen
JB, Parmar
M, Guillemot
F
&
Bjorklund
A (2006a). Development of the mesencephalic dopaminergic neuron system is compromised in the absence of neurogenin 2. Development
133, 507–516.
Andersson E, Tryggvason U, Deng Q, Friling S, Alekseenko Z, Robert B, Perlmann T & Ericson J (2006b). Identification of intrinsic determinants of midbrain dopamine neurons. Cell 124, 393–405.[CrossRef][Medline]
Arber S, Ladle DR, Lin JH, Frank E & Jessell TM (2003). ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell 101, 485–498.[CrossRef]
Arlotta P, Molyneaux BJ, Chen J, Inoue J, Kominami R & Macklis JD (2005). Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo. Neuron 45, 207–221.[CrossRef][Medline]
Bennett MR & Balcar VJ (1999). Forty years of amino acid transmission in the brain. Neurochem Int 35, 269–280.[CrossRef][Medline]
Bertrand N, Castro DS & Guillemot F (2002). Proneural genes and the specification of neural cell types. Nat Rev Neuroscience 3, 517–530.[CrossRef][Medline]
Blackshaw S, Harpavat S, Trimarchi J, Cai L, Huang H, Kuo WP, Weber G, Lee K, Fraioli RE, Cho SH, Yung R, Asch E, Ohno-Machado L, Wong WH & Cepko CL (2004). Genomic analysis of mouse retinal development. Plos Biol 2, E247.[CrossRef][Medline]
Borodinsky LN, Root CM, Cronin JA, Sann SB, Gu X & Spitzer NC (2004). Activity-dependent homeostatic specification of transmitter expression in embryonic neurons. Nature 429, 523–530.
Brunet J & Ghysen A (1999). Deconstructing cell determination: proneural genes and neuronal identity. Bioessays 21, 313–318.[CrossRef][Medline]
Brunet JF & Pattyn A (2002). Phox2 genes – from patterning to connectivity. Curr Opin Genet Dev 12, 435–440.[CrossRef][Medline]
Buck LB (2000). The molecular architecture of odor and pheromone sensing in mammals. Cell 100, 611–618.[CrossRef][Medline]
Casarosa S, Fode C & Guillemot F (1999). Mash1 regulates neurogenesis in the ventral telencephalon. Development 126, 525–534.[Abstract]
Cau E, Casarosa S & Guillemot F (2002). Mash1 and Ngn1 control distinct steps of determination and differentiation in the olfactory sensory neuron lineage. Development 129, 1871–1880.[Medline]
Chen AI, de Nooij JC & Jessell TM (2006a). Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord. Neuron 49, 395–408.[CrossRef][Medline]
Chen
B, Schaevitz
LR
&
McConnell
SK (2005). Fezl regulates the differentiation and axon targeting of layer 5 subcortical projection neurons in cerebral cortex. Proc Natl Acad Sci U S A
102, 17184–17189.
Chen CL, Broom DC, Liu Y, de Nooij JC, Li Z, Cen C, Samad OA, Jessell TM, Woolf CJ & Ma Q (2006b). Runx1 determines nociceptive sensory neuron phenotype and is required for thermal and neuropathic pain. Neuron 49, 365–377.[CrossRef][Medline]
Cheng L, Arata A, Mizuguchi R, Qian Y, Karunaratne A, Gray PA, Arata S, Shirasawa S, Bouchard M, Luo P, Chen CL, Busslinger M, Goulding M, Onimaru H & Ma Q (2004). Tlx3 and Tlx1 are post-mitotic selector genes determining glutamatergic over GABAergic cell fates. Nat Neurosci 7, 510–517.[CrossRef][Medline]
Cheng
L, Chen
CL, Luo
P, Tan
M, Qiu
M, Johnson
R
&
Ma
Q (2003). Lmx1b, Pet-1, and Nkx2.2 coordinately specify serotonergic neurotransmitter phenotype. J Neurosci
23, 9961–9967.
Cheng L, Samad OA, Xu Y, Mizuguchi R, Luo P, Shirasawa S, Goulding M & Ma Q (2005). Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes. Nat Neurosci 8, 1510–1515.[CrossRef][Medline]
Cobos I, Calcagnotto ME, Vilaythong AJ, Thwin MT, Noebels JL, Baraban SC & Rubenstein JL (2005). Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy. Nat Neurosci 8, 1059–1068.[CrossRef][Medline]
Dasen JS, Tice BC, Brenner-Morton S & Jessell TM (2005). A Hox regulatory network establishes motor neuron pool identity and target-muscle connectivity. Cell 123, 477–491.[CrossRef][Medline]
Ding YQ, Marklund U, Yuan W, Yin J, Wegman L, Ericson J, Deneris E, Johnson RL & Chen ZF (2003). Lmx1b is essential for the development of serotonergic neurons. Nat Neurosci 6, 933–938.[CrossRef][Medline]
Eng
SR, Lanier
J, Fedtsova
N
&
Turner
EE (2004). Coordinated regulation of gene expression by Brn3a in developing sensory ganglia. Development
131, 3859–3870.
Esumi S, Kakazu N, Taguchi Y, Hirayama T, Sasaki A, Hirabayashi T, Koide T, Kitsukawa T, Hamada S & Yagi T (2005). Monoallelic yet combinatorial expression of variable exons of the protocadherin-alpha gene cluster in single neurons. Nat Genet 37, 171–176.[CrossRef][Medline]
Fode C, Gradwohl G, Morin X, Dierich A, LeMeur M, Goridis C & Guillemot F (1998). The bHLH protein NEUROGENIN2 is a detemination factor for epibranchial placode-derived sensory neurons. Neuron 120, 483–494.
Fode
C, Ma
Q, Casarosa
S, Ang
S-L, Anderson
DJ
&
Guillemot
F (2000). A role for neural determination genes in specifying the dorsoventral identity of telencephalic neurons. Genes Dev
14, 67–80.
Francis NJ & Landis SC (1999). Cellular and molecular determinants of sympathetic neuron development. Annu Rev Neurosci 22, 541–566.[CrossRef][Medline]
Fremeau RTJ, Voglmaier S, Seal RP & Edwards RH (2004). VGLUTs define subsets of excitatory neurons and suggest novel roles for glutamate. Trends Neurosci 27, 98–103.[Medline]
Furukawa T, Morrow EM & Cepko CL (1997). Crx, a novel otx-like homeobox gene, shows photoreceptor-specific expression and regulates photoreceptor differentiation. Cell 91, 531–541.[CrossRef][Medline]
Gaudilliere B, Konishi Y, de la Iglesia N, Yao G & Bonni A (2004). A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis. Neuron 41, 229–241.[CrossRef][Medline]
Gerber
AN, Klesert
TR, Bergstrom
DA
&
Tapscott
SJ (1997). Two domains of MyoD mediate transcriptional activation of genes in repressive chromatin: a mechanism for lineage determination in myogenesis. Genes Dev
11, 436–450.
Glasgow
SM, Henke
RM, Macdonald
RJ, Wright
CV
&
Johnson
JE (2005). Ptf1a determines GABAergic over glutamatergic neuronal cell fate in the spinal cord dorsal horn. Development
132, 5461–5469.
Goridis C & Rohrer H (2002). Specification of catecholaminergic and serotonergic neurons. Nat Rev Neurosci 3, 531–541.[CrossRef][Medline]
Gowan K, Helms AW, Hunsaker TL, Collisson T, Ebert PJ, Odom R & Johnson JE (2001). Crossinhibitory activities of Ngn1 and Math1 allow specification of distinct dorsal interneurons. Neuron 31, 219–232.[CrossRef][Medline]
Gradwohl G, Fode C & Guillemot F (1996). Restricted expression of a novel murine atonal-related bHLH protein in undifferentiated neural precursors. Dev Biol 180, 227–241.[CrossRef][Medline]
Gray
PA, Fu
H, Luo
P, Zhao
Q, Yu
J, Ferrari
A
et al. (2004). Mouse brain organization revealed through direct genome-scale TF expression analysis. Science
306, 2255–2257.
Gross MK, Dottori M & Goulding M (2002). Lbx1 specifies somatosensory association interneurons in the dorsal spinal cord. Neuron 34, 535–549.[CrossRef][Medline]
Guillemot F, Lo LC, Johnson JE, Auerbach A, Anderson DJ & Joyner AL (1993). Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell 75, 463–476.[CrossRef][Medline]
Guillemot F, Molnar Z, Tarabykin V & Stoykova A (2006). Molecular mechanisms of cortical differentiation. Eur J Neurosci 23, 857–868.[CrossRef][Medline]
Gutierrez R (2003). The GABAergic phenotype of the ‘glutamatergic’ granule cells of the dentate gyrus. Prog Neurobiol 71, 337–358.[CrossRef][Medline]
Hand R, Bortone D, Mattar P, Nguyen L, Heng JI, Guerrier S et al. (2005). Phosphorylation of Neurogenin2 specifies the migration properties and the dendritic morphology of pyramidal neurons in the neocortex. Neuron 48, 45–62.[CrossRef][Medline]
Helms
AW, Battiste
J, Henke
RM, Nakada
Y, Simplicio
N, Guillemot
F
&
Johnson
JE (2005). Sequential roles for Mash1 and Ngn2 in the generation of dorsal spinal cord interneurons. Development
132, 2709–2719.
Helms AW & Johnson JE (2003). Specification of dorsal spinal cord interneurons. Curr Op Neurobiol 13, 42–49.[CrossRef][Medline]
Hendricks
T, Francis
N, Fyodorov
D
&
Deneris
ES (1999). The ETS domain factor Pet-1 is an early and precise marker of central serotonin neurons and interacts with a conserved element in serotonergic genes. J Neurosci
19, 10348–10356.
Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B et al. (2003). Pet-1 ETS gene plays a critical role in 5-HT neuron development and is required for normal anxiety-like and aggressive behavior. Neuron 37, 233–247.[CrossRef][Medline]
Hirsch M-R, Tiveron M-C, Guillemot F, Brunet J-F & Goridis C (1998). Control of noradrenergic differentiation and Phox2a expression by MASH1 in the central and peripheral nervous system. Development 125, 599–608.[Abstract]
Hoshino MM, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura Y et al. (2005). Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum. Neuron 47, 201–213.[CrossRef][Medline]
Howard MJ (2005). Mechanisms and perspectives on differentiation of autonomic neurons. Dev Biol 277, 271–286.[CrossRef][Medline]
Hsieh J & Gage FH (2005). Chromatin remodeling in neural development and plasticity. Curr Opin Cell Biol 17, 664–671.[CrossRef][Medline]
Jan L & Jan YN (1993). HLH proteins, fly neurogenesis, and vertebrate myogenesis. Cell 75, 827–830.[CrossRef][Medline]
Jeong
JY, Einhorn
Z, Mercurio
S, Lee
S, Lau
B, Mione
M, Wilson
SW
&
Guo
S (2006). Neurogenin1 is a determinant of zebrafish basal forebrain dopaminergic neurons and is regulated by the conserved zinc finger protein Tof/Fezl. Proc Natl Acad Sci U S A
103, 5143–5148.
Jessell TM (2000). Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet 1, 20–29.[CrossRef][Medline]
Kaern M, Elston TC, Blake WJ & Collins JJ (2005). Stochasticity in gene expression: from theories to phenotypes. Nat Rev Genet 6, 451–464.[CrossRef][Medline]
Kandel ER, Schwartz JH & Jessell TM (2000). Principles of Neural Science. McGraw-Hill New York, U S A.
Kele
J, Simplicio
N, Ferri
AL, Mira
H, Guillemot
F, Arenas
E
&
Ang
SL (2006). Neurogenin 2 is required for the development of ventral midbrain dopaminergic neurons. Development
133, 495–505.
Kiecker C & Lumsden A (2005). Compartments and their boundaries in vertebrate brain development. Nat Rev Neurosci 6, 553–564.[CrossRef][Medline]
Kim JH, Auerbach JM, Rodriguez-Gomez JA, Velasco I, Gavin D, Lumelsky N et al. (2002). Dopamine neurons derived from embryonic stem cells function in an animal model of Parkinson's disease. Nature 418, 50–56.
Koshiba-Takeuchi
K, Takeuchi
JK, Matsumoto
K, Momose
T, Uno
K, Hoepker
V
et al. (2000). Tbx5 and the retinotectum projection. Science
287, 134–137.
Koyano-Nakagawa N, Wettstein D & Kintner C (1999). Activation of Xenopus genes required for lateral inhibition and neuronal differentiation during primary neurogenesis. Mol Cell Neurosci 14, 327–339.[CrossRef][Medline]
Kramer I, Sigrist M, de Nooij JC, Taniuchi I, Jessell TM & Arber S (2006). A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification. Neuron 49, 379–393.[CrossRef][Medline]
Lee JE (1997). NeuroD and neurogenesis. Dev Neuroscience 19, 27–32.[Medline]
Lee
JE, Hollenberg
SM, Snider
L, Turner
DL, Lipnick
N
&
Weintraub
H (1995). Conversion of Xenopus ectoderm into neurons by NeuroD, a basic-helix-loop-helix protein. Science
268, 836–844.
Lee SK & Pfaff SL (2001). Transcriptional networks regulating neuronal identity in the developing spinal cord. Nat Neurosci 4, 1183–1191.[CrossRef][Medline]
Li Q, Harju S & Peterson KR (1999). Locus control regions: coming of age at a decade plus. Trends Genet 15, 403–408.[CrossRef][Medline]
Li MZ, Wang JS, Jiang DJ, Xiang CX, Wang FY, Zhang KH, Williams PR & Chen ZF (2006). Molecular mapping of developing dorsal horn-enriched genes by microarray and dorsal/ventral subtractive screening. Dev Biol 292, 555–564.[CrossRef][Medline]
Livesey FJ & Cepko CL (2001). Vertebrate neural cell-fate determination: lessons from the retina. Nat Rev Neurosci 2, 109–118.[CrossRef][Medline]
Ma Q, Chen Z, del Barco Barrantes I, de la Pompa JL & Anderson DJ (1998). neurogenin1 is essential for the determination of neuronal precursors for proximal cranial sensory ganglia. Neuron 20, 469–482.[CrossRef][Medline]
Ma
Q, Fode
C, Guillemot
F
&
Anderson
DJ (1999). Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia. Genes Dev
13, 1717–1728.
Ma Q, Kintner C & Anderson DJ (1996). Identification of neurogenin, a vertebrate neuronal determination gene. Cell 87, 43–52.[CrossRef][Medline]
Ma
Q, Sommer
L, Cserjesi
P
&
Anderson
DJ (1997). Mash1 and neurogenin1 expression patterns define complementary domains of neuroepithelium in the developing CNS and are correlated with regions expressing notch ligands. J Neurosci
17, 3644–3652.
McConnell SK (1995). Constructing the cerebral cortex: neurogenesis and fate determination. Neuron 15, 761–768.[CrossRef][Medline]
McNay
DE, Pelling
M, Claxton
S, Guillemot
F
&
Ang
SL (2006). Mash1 is required for generic and subtype differentiation of hypothalamic neuroendocrine cells. Mol Endocrinol
20, 1623–1632.
Maier H, Ostraat R, Gao H, Fields S, Shinton SA, Medina KL et al. (2004). Early B cell factor cooperates with Runx1 and mediates epigenetic changes associated with mb-1 transcription. Nature Immunol 5, 1069–1077.[CrossRef][Medline]
Mann RS & Carroll SB (2002). Molecular mechanisms of selector gene function and evolution. Curr Opin Genet Dev 12, 592–600.[CrossRef][Medline]
Marmigere F, Montelius A, Wegner M, Groner Y, Reichardt LF & Ernfors P (2006). The Runx1/AML1 transcription factor selectively regulates development and survival of TrkA nociceptive sensory neurons. Nat Neurosci 9, 180–187.[CrossRef][Medline]
Masland RH (2004). Neuronal cell types. Curr Biol 14, R497–R500.[CrossRef][Medline]
Mattick
JS
&
Makunin
IV (2005). Small regulatory RNAs in mammals. Hum Mol Genet
14, R121–R132.
Miyoshi
G, Bessho
Y, Yamada
S
&
Kageyama
R (2004). Identification of a novel basic helix-loop-helix gene, Heslike, and its role in GABAergic neurogenesis. J Neurosci
24, 3672–3682.
Mizuguchi R, Kriks S, Cordes R, Gossler A, Ma Q & Goulding M (2006). Ascl1 and Gsh1/2 control inhibitory and excitatory cell fate in spinal sensory interneurons. Nat Neurosci 9, 770–778.[CrossRef][Medline]
Molyneaux BJ, Arlotta P, Hirata T, Hibi M & Macklis JD (2005). Fezl is required for the birth and specification of corticospinal motor neurons. Neuron 47, 817–831.[CrossRef][Medline]
Mui
SH, Hindges
R, O'Leary
DD, Lemke
G
&
Bertuzzi
S (2002). The homeodomain protein Vax2 patterns the dorsoventral and nasotemporal axes of the eye. Development
129, 797–804.
Muller
T, Anlag
K, Wildner
H, Britsch
S, Treier
M
&
Birchmeier
C (2005). The bHLH factor Olig3 coordinates the specification of dorsal neurons in the spinal cord. Genes Dev
19, 733–743.
Müller T, Brohmann H, Pierani A, Heppenstall PA, Lewin GR, Jessell TM & Birchmeier C (2002). The homeodomain factor Lbx1 distinguishes two major programs of neuronal differentiation in the dorsal spinal cord. Neuron 34, 551–562.[CrossRef][Medline]
Nakagawa
Y
&
O'Leary
DD (2001). Combinatorial expression patterns of LIM-homeodomain and other regulatory genes parcellate developing thalamus. J Neurosci
21, 2711–2725.
Navarro M & Gull K (2001). A pol I transcriptional body associated with VSG mono-allelic expression in Trypanosoma brucei. Nature 414, 759–763.
Pak W, Hindges R, Lim YS, Pfaff SL & O'Leary DD (2004). Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Cell 119, 567–578.[CrossRef][Medline]
Parras
CM, Schuurmans
C, Scardigli
R, Kim
J, Anderson
DJ
&
Guillemot
F (2002). Divergent functions of the proneural genes Mash1 and Ngn2 in the specification of neuronal subtype identity. Genes Dev
16, 324–338.
Parrish
JZ, Kim
MD, Jan
LY
&
Jan
YN (2006). Genome-wide analyses identify transcription factors required for proper morphogenesis of Drosophila sensory neuron dendrites. Genes Dev
20, 820–835.
Pattyn A, Simplicio N, van Doorninck JH, Goridis C, Guillemot F & Brunet JF (2004). Ascl1/Mash1 is required for the development of central serotonergic neurons. Nat Neurosci 7, 589–595.[CrossRef][Medline]
Perez SE, Rebelo S & Anderson DJ (1999). Early specification of sensory neuron fate revealed by expression and function of neurogenins in the chick embryo. Development 126, 1715–1728.[Abstract]
Ramirez M & Gutierrez R (2001). Activity-dependent expression of GAD67 in the granule cells of the rat hippocampus. Brain Res 917, 139–146.[CrossRef][Medline]
Raser
JM
&
O'Shea
EK (2005). Noise in gene expression: origins, consequences, and control. Science
309, 2010–2013.
Represa A & Ben-Ari Y (2005). Trophic actions of GABA on neuronal development. Trends Neurosci 28, 278–283.[CrossRef][Medline]
Sandberg M, Kallstrom M & Muhr J (2005). Sox21 promotes the progression of vertebrate neurogenesis. Nat Neurosci 8, 995–1001.[CrossRef][Medline]
Schulte D, Furukawa T, Peters MA, Kozak CA & Cepko CL (1999). Misexpression of the Emx-related homeobox genes cVax and mVax2 ventralizes the retina and perturbs the retinotectal map. Neuron 24, 541–553.[CrossRef][Medline]
Schuurmans C, Armant O, Nieto M, Stenman JM, Britz O, Klenin N et al. (2004). Sequential phases of cortical specification involve Neurogenin-dependent and -independent pathways. EMBO J 23, 2892–2902.[CrossRef][Medline]
Schuurmans C & Guillemot F (2002). Molecular mechanisms underlying cell fate specification in the developing telencephalon. Curr Opin Neurobiol 12, 26–34.[CrossRef][Medline]
Schwarzer C & Sperk G (1995). Hippocampal granule cells express glutamic acid decarboxylase-67 after limbic seizures in the rat. Neuroscience 69, 705–709.[CrossRef][Medline]
Serizawa
S, Miyamichi
K, Nakatani
H, Suzuki
M, Saito
M, Yoshihara
Y
&
Sakano
H (2003). Negative feedback regulation ensures the one receptor-one olfactory neuron rule in mouse. Science
302, 2078–2079.
Shykind
BM (2005). Regulation of odorant receptors: one allele at a time. Hum Mol Genet
14, R33–R39.
Sloviter RS, Dichter MA, Rachinsky TL, Dean E, Goodman JH, Sollas AL & Martin DL (1996). Basal expression and induction of glutamate decarboxylase and GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus. J Comp Neurol 373, 593–618.[CrossRef][Medline]
Smallwood
PM, Wang
Y
&
Nathans
J (2002). Role of a locus control region in the mutually exclusive expression of human red and green cone pigment genes. Proc Natl Acad Sci U S A
99, 1008–1011.
Sommer L, Ma Q & Anderson DJ (1996). Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogenity in the developing CNS and PNS. Mol Cell Neurosci 8, 221–241.[CrossRef][Medline]
Spitzer NC, Root CM & Borodinsky LN (2004). Orchestrating neuronal differentiation: patterns of Ca2+ spikes specify transmitter choice. Trends Neurosci 27, 415–421.[CrossRef][Medline]
Sun Y, Nadal-Vicens M, Misono S, Lin MZ, Zubiaga A, Hua X, Fan G & Greenberg ME (2001). Neurogenin promotes neurogenesis and inhibits glial differentiation by independent mechanisms. Cell 104, 365–376.[CrossRef][Medline]
Sur
M
&
Rubenstein
JL (2005). Patterning and plasticity of the cerebral cortex. Science
310, 805–810.
Tanabe Y, William C & Jessell TM (1998). Specification of motor neuron identity by the MNR2 homeodomain protein. Cell 95, 67–80.[CrossRef][Medline]
Tapscott
SJ (2005). The circuitry of a master switch: Myod and the regulation of skeletal muscle gene transcription. Development
132, 2685–2695.
Thiel G (2006). Transcription Factors in the Nervous System. Wiley-VCH-Verlag GmbH Weinheim.
Vitalis T & Parnavelas JG (2003). The role of serotonin in early cortical development. Dev Neurosci 25, 245–256.[CrossRef][Medline]
Weimann JM, Zhang YA, Levin ME, Devine WP, Brulet P & McConnell SK (1999). Cortical neurons require Otx1 for the refinement of exuberant axonal projections to subcortical targets. Neuron 24, 819–831.[CrossRef][Medline]
Weintraub H (1993). The MyoD family and myogenesis: redundancy, networks, and thresholds. Cell 75, 1241–1244.[CrossRef][Medline]
Wichterle H, Lieberam I, Porter JA & Jessell TM (2002). Directed differentiation of embryonic stem cells into motor neurons. Cell 110, 385–397.[CrossRef][Medline]
Wildner
H, Muller
T, Cho
SH, Brohl
D, Cepko
CL, Guillemot
F
&
Birchmeier
C (2006). dILA neurons in the dorsal spinal cord are the product of terminal and non-terminal asymmetric progenitor cell divisions, and require Mash1 for their development. Development
133, 2105–2113.
Zhu X, Lin CR, Prefontaine GG, Tollkuhn J & Rosenfeld MG (2005). Genetic control of pituitary development and hypopituitarism. Curr Opin Genet Dev 15, 332–340.[CrossRef][Medline]
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