This Title All WIREs
How to cite this WIREs title:
WIREs Dev Biol
Impact Factor: 5.814

Transcriptional selectors, masters, and combinatorial codes: regulatory principles of neural subtype specification

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

The broad range of tissue and cellular diversity of animals is generated to a large extent by the hierarchical deployment of sequence‐specific transcription factors and co‐factors (collectively referred to as TF's herein) during development. Our understanding of these developmental processes has been facilitated by the recognition that the activities of many TF's can be meaningfully described by a few functional categories that usefully convey a sense for how the TF's function, and also provides a sense for the regulatory organization of the developmental processes in which they participate. Here, we draw on examples from studies in Caenorhabditis elegans, Drosophila melanogaster, and vertebrates to discuss how the terms spatial selector, temporal selector, tissue/cell type selector, terminal selector and combinatorial code may be usefully applied to categorize the activities of TF's at critical steps of nervous system construction. While we believe that these functional categories are useful for understanding the organizational principles by which TF's direct nervous system construction, we however caution against the assumption that a TF's function can be solely or fully defined by any single functional category. Indeed, most TF's play diverse roles within different functional categories, and their roles can blur the lines we draw between these categories. Regardless, it is our belief that the concepts discussed here are helpful in clarifying the regulatory complexities of nervous system development, and hope they prove useful when interpreting mutant phenotypes, designing future experiments, and programming specific neuronal cell types for use in therapies. WIREs Dev Biol 2015, 4:505–528. doi: 10.1002/wdev.191 This article is categorized under: Nervous System Development > Worms Nervous System Development > Flies Nervous System Development > Vertebrates: General Principles
Terminal selectors. (a) The original definition of terminal selector genes focused on one or two TF's acting to direct a whole gene battery that uniquely identifies a specific neuronal subtype. For example, for cell subtypes 1 and 2, these neurons differ in the combination of TF's that synergistically activate most effector genes that are together unique to that neuronal subtype. In many other cases, terminal selectors can fall into two other categories. Comparing subtype A and B, a subroutine comprising most effector genes controlling neurotransmitter identity or axon pathfinding may be controlled by a combination of TF's that act as a terminal selector for that subroutine, but may not be used in other subtypes for their neurotransmitter or pathfinding. In parallel, single TF's (such as Dimmed or DAF‐19) may singularly direct a battery of genes for a specific subroutine that is common to many neuronal subtypes, such as for neurosecretory phenotype (as for Drosophila Dimmed) or a ciliated sensory morphology (as for C. elegans DAF‐19). (b) An example of a combinatorial code of TF's acting to dictate critical aspects of unique subtype identity. In the Drosophila ventral nerve cord (VNC) a set of TF's are expressed in subsets of Apterous neurons. While these TF's are expressed by many other neurons, their combinatorial co‐expression is unique to two neuronal subtypes; the Tv neurons that express the FMRFa neuropeptide, and the Tvb and dAp neurons that express the Nplp1 neuropeptide. Mutants for any of these TF's disrupt establishment of cell fate. (i–vi) Combinatorial CNS‐wide misexpression of these TF's can trigger widespread neuropeptide expression. The Nplp1 expression code consists of Ap (Apterous), Dimm (Dimmed), and Col (Collier). The FMRFa expression code consists of Ap, Dimm, and Dac (see Ref for more details). In these same cells, Dimm further acts as a terminal selector for a gene battery controlling neurosecretory function. Importantly, each triple code selectively activates one neuropeptide and not the other, in spite of the mere substitution of one TF.
[ Normal View | Magnified View ]
Tissue/cell type selectors. (a) In Drosophila, during the process of Notch‐mediated lateral inhibition, NBs (in CNS) and SOPs (in PNS) are selected from an equivalence group of cells. Critical for their neural progenitor identity is the expression of proneural TF's, which establish many features of early NBs and SOPs. However, studies reveal that different proneural members are expressed by different progenitors, with a general theme of Ac, Sc, and L'sc in the CNS, and Ato and Amos in the PNS. (b) In vertebrates, the proneural gene Ascl1 is expressed in a number of dorsal progenitor domains. Ascl1 activates Tlx1 and Tlx3 in postmitotic neurons dILB and dI5, and the Tlx TF's have a direct role as terminal selectors in activating their glutamatergic neurotransmitter identity. The expression of Tlx1 and Tlx3 further represses an alternate GABAergic fate by repressing Pax2. Ascl1 also activates Ptf1a expression after a Notch‐mediated delay. Ptf1a serves a dual function. It activates Prdm13, which interferes with Ascl1 transcriptional activity to repress its function. It also activates Lhx1/5 and Pax2 among other TF's to promote the generation of dILA and dI4 GABAergic neurons. Thus, Ascl1 establishes an opposing loop to establish glutamatargic and GABAergic fates for postmitotic neurons. (c) Gcm is a cell type selector for glial cell fate. In thoracic segments, the neuroblast NB6‐4T generates glial cells and neurons. NB6‐4 initially expresses cytoplasmic Gcm (purple ring), but after the first NB division the resulting ganglion mother cell (GMC) increases Gcm expression, which becomes nuclear and drives glial cell generation in the progeny of that cell. In gcm mutants, no glial cells are generated by NB6‐4T. When gcm is overexpressed in the lineage, glial cells are generated at the expense of neurons.
[ Normal View | Magnified View ]
Temporal selectors. (a) In the Drosophila embryo, most if not all NBs undergo a stereotyped sequential progression of temporal selector expression, from Hb (Hunchback), to Kr (Kruppel) to Pdm (POU‐homeodomain), to Cas (Castor) and to Grh (Grainy head). Note that the expression of each temporal selector may persist through several NB divisions and may also overlap (not shown here). In each case, the GMC (ganglion mother cell) and neurons/glia arising from each NB is marked by the temporal selector expressed from its parental NB. The temporal selectors are cross‐regulatory (shown by activation and repression arrows), but additional switching factors participate in the transition between temporal selectors. These include Dan (distal antenna) and Svp (Seven up) switching factors which ensure timely downregulation of Hb. A subset of lineages (as shown here from NB5‐6T) re‐express Svp and/or express the subtemporal TF's Sqz and Nab, which act to subdivide larger temporal windows, such as the Cas window in NB5‐6T. The majority of embryonic NB lineages start off in the Type I proliferation mode wherein one GMC is generated that generates two daughter cells, but most lineages then switch to Type 0 mode, wherein no GMC is generated. (b) In larvae, post‐embryonic neuroblast lineages show greater diversity in lineage progression and temporal selector cascades. Studies have identified several alternate temporal selector cascades, which involve mostly different TF's than those observed in the embryo. (top) In the optic lobe, two different cascades have been identified, controlling temporal progression in different parts of the lobe. (bottom) In the central brain, a specialized subset of NBs exist, Type II NBs, which generate a proliferative daughter cell; the intermediate neural progenitor (INP). Intriguingly, the NB and INPs express distinct temporal cascades. Neighboring temporal selectors are often co‐expressed during the transition from one to the next (not depicted). Black arrows refer to temporal flow, while red arrows refer to regulatory interactions (see main text for details).
[ Normal View | Magnified View ]
Spatial selectors. (a and b) In the early Drosophila embryo, some 1200 NBs are formed, and are exposed to spatial selector information. (a; Right) The role of spatial selectors that determine intra‐segmental A–P identity, exemplified here by expression of Gsb (green). In each hemisegment, Gsb is expressed by a subset of NBs, all in rows 5 and 6, and two in row 7. Ftz and Hkb mark other subsets (a few examples are shown here). In gsb mutants, row 5 identity is lost, and Ftz and Hkb become expressed by some row 5 NBs. Conversely, when gsb is misexpressed, row 3 and 4 NBs acquire row 5 identity (see for more detail and references). (b) Generation of spatial selector compartments in the developing vertebrate neural tube. Morphogen gradients are established across neural tube neuroepithelial cells by Sonic hedgehog (SHH) from the notochord and floorplate, and Bone morphogenetic proteins (BMPs) from the roofplate. SHH establishes initially broad domains of expression of opposing Class I (blue; repressed by SHH) and Class II (red; activated by SHH) TF's. Class I and Class II TF's, whose threshold for repression or activation appose one another at a specific D–V step, are mutually antagonistic. This cross‐repression results in sharp boundaries for their expression. Across a number of antagonistic TF pairs, a set of six compartments (denoted p3 ventrally to pd6 more dorsally) of proliferating progenitors are generated, each with distinct combinations of TF's. Each progenitor compartment then generates distinct sets of postmitotic neurons. For example, the pMN compartment generates motor neurons that initially all express Isl1 and Mnx1. (b; Right panels) Olig2 loss and gain‐of‐function tests, showing the ventral half neural tube. Upper panel shows Olig1 and Olig2 double mutants (Olig2 LOF). In this mutant, the cross‐repressive partner for Olig2, Irx3, expands ventrally into the pMN compartment. This reprograms the pMN compartment to a p2 compartment identity that generates an excess of Vsx2‐expressing interneurons at the expense of motor neurons. Lower panel shows Olig2 gain‐of‐function (Olig2 GOF). Motor neurons are generated more dorsally due in part to repression of Irx3 within ventral regions, as well as loss of En1 and Emx1‐type neurons. Intriguingly, Vsx2 expression is shifted more dorsally due to Olig2‐mediated activation of Lhx3, which is required in motor neurons for their generation, but also in Vsx2 interneurons for their differentiation.
[ Normal View | Magnified View ]
Selector categories exemplified in the Drosophila embryo. (a) Spatial selector patterning of the neuroectoderm and delaminating neuroblasts. Shown are examples (rather than a complete map) of spatial selectors. These include spatial selectors along the entire A–P axis (anterior gap genes and Hox genes), whose expression pattern is represented by the bars alongside the embryo. These include gap genes Otd (Orthodenticle) and Ems (Empty spiracles), and the Hox genes Lab (Labial), Dfd (Deformed), Scr (Sex combs reduced), Antp (Antennapedia), Ubx (Ultrabithorax), Abd‐A (Abdominal‐A), and Abd‐B (Abdominal‐B). Also in the A–P axis, each segment is compartmentalized by segment polarity genes, as exemplified by the banding patterns of Gsb (magenta; Gooseberry) and En (blue; Engrailed). In the D–V axis, neuroectodermal and neuroblast compartments are mapped out by Vnd (ventral nervous system defective), Ind (intermediate nervous system defective), and Msh (muscle specific homeobox). The mesectoderm that forms the midline is determined by the spatial selector Sim (red band along midline; Simple minded). (b) Temporal selectors. During neuroblast proliferation, shifts in a temporal sequence of TF's occur over time that alter the developmental program of the lineage through time; such temporal selectors are depicted by the transition from Kr (pink; Kruppel) (pink) to Pdm (green; POU‐homeodomain). (c) Tissue/cell type selector. During progenitor lineage progression, the type selector Gcm commits subsets of progenitors to a lateral glial cell fate. (d) Terminal selector. In postmitotic neurons, the terminal selector Dimmed activates a battery of genes that are together required for neuroendocrine identity and function for subsets of neurons.
[ Normal View | Magnified View ]

Browse by Topic

Nervous System Development > Vertebrates: General Principles
Nervous System Development > Flies
Nervous System Development > Worms