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First published online October 10, 2008
doi: 10.1242/10.1242/dev.016931

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Temporal control of neuronal diversity: common regulatory principles in insects and vertebrates?

¹ Division of Developmental Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
² National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK.

View larger version (72K): [in this window] [in a new window]   Fig. 1. Progenitor temporal transcription factors (TTFs) in Drosophila. Wild-type (wt) Drosophila neuroblasts (large circles) express four progenitor TTFs, at different times during embryogenesis, in the following sequence: Hunchback (Hb) Kruppel (Kr) Pdm Castor (Cas). (A) Each progenitor TTF is associated with postmitotic progeny (small circles) of a different temporal identity (blue, red, yellow or green). (a) Loss-of-function of a single progenitor TTF leads either to the skipping of one temporal identity (shown in grey for hb-/-, Kr-/- or pdm-/-) or to stalled temporal series progression, associated with supernumerary early temporal identities that are Pdm-dependent (cas-/-) or Hb-dependent (svp-/-). (b) Continuous misexpression of any of the four progenitor TTFs leads to supernumerary progeny with the corresponding temporal identity. (B) Known negative cross-regulatory interactions between progenitor TTFs and the switching factor Svp. Cas is not only a progenitor TTF but, like Svp, also a switching factor (red). Note that other known progenitor TTFs (black), such as Hb, do not fulfil this definition because although misexpression blocks progenitor TTF progression, loss-of-function does not (Grosskortenhaus et al., 2005; Isshiki et al., 2001). (C) Progenitor TTFs are also expressed during postembryonic (larval and pupal) stages. Most, if not all, neuroblasts first generate Chinmo+ (blue) neurons during embryonic and early larval stages. They then switch to producing Broad-Complex+ (pink) neurons during late larval and pupal stages. Neuroblasts fail to undergo the Chinmo+ Br-C+ switch if the postembryonic progression of progenitor TTFs is blocked by the removal of the postembryonic (PE) pulse of Cas (PE cas-/-) or of Svp (PE svp-/-), or by misexpressing Cas (PE + cas).

View larger version (38K): [in this window] [in a new window]   Fig. 2. Postmitotic TTFs in Drosophila and mammals. (A) In Drosophila, wild-type (wt) mushroom body (MB) neuroblasts (large circles) generate MB neurons (small circles). Early-born MB neurons express high levels of the transcription factor Chinmo (dark blue), whereas later-born MB neurons express either low levels (light blue) or none (white). Postmitotic levels of Chinmo specify the different temporal identities of , '/β', p/β or /β neurons. A decrease in Chinmo expression (Chinmo-) leads to fewer neurons and to the precocious generation of supernumerary p/β neurons. Chinmo does not appear to specify the temporal identity of /β neurons. If high levels of Chinmo are maintained in all postmitotic neurons (+ Chinmo), the early temporal identity () is continuously generated at the expense of all later temporal identities ('/β', p/β and /β). (B) (a) In the mouse cerebral cortex, multipotent progenitors (mP) generate two distinct pools of progenitors: deep-layer progenitors (dP) and superficial-layer progenitors (sP). In turn, dP and sP sequentially generate the different neuronal subtypes (coloured circles) that are associated with deep (SP/VI/V) and superficial (IV/III/II) cortical layers, respectively. Postmitotic projection neurons of the different layers express different combinations of Sox5 (SRY-box 5), Ctip2 (Coup-TF-interacting protein 2) and Satb2 (special AT-rich sequence binding protein 2). Sox5 is normally expressed at different levels in the neurons of each of the layers SP, VI and V. (b) Sox5 inactivation leads to a reduction in the sub-plate (SP) neuronal layer. SP neurons appear to be replaced by ectopic Ctip2+ neurons (yellow), characteristic of layer V. For clarity, ectopic Ctip2+ neurons located in superficial layers IV/III/II have been omitted as their origin is unclear. Inactivation of Satb2, which is predominantly expressed by layer IV/III/II neurons, leads to these late-born neurons acquiring an earlier Ctip2+ identity. (c) Sox5 and Satb2 repress Ctip2, and biochemical studies suggest that the Satb2 repression is direct (Alcamo et al., 2008; Britanova et al., 2008). As Ctip2 and Satb2 are transiently coexpressed by some layer V neurons (Alcamo et al., 2008), it might be that a stable layer-specific cell identity is only acquired sometime after neurons become postmitotic.

View larger version (47K): [in this window] [in a new window]   Fig. 3. Candidate progenitor TTFs in vertebrates. (A) (a) In most rhombomeres (r) of wild-type (wt) mouse and chick hindbrains, ventral progenitors (large circles) express Phox2b (Px2b) early and then Foxa2 (Fxa2) later, correspondingly generating VM (yellow) then 5HT (red) neurons. In Phox2b-/- mice, progenitors express Foxa2 and generate 5HT neurons precociously. In Foxa2-/- mice, VM generation is prolonged. (b) Loss- and gain-of-function experiments show that it is sequential cross-repression that promotes the switch between the VM and 5HT neuronal identities. (c) Hoxb1 (Hxb1) expression in r4 maintains Phox2b expression, thus preventing the switch to 5HT neurogenesis in this particular segment of the hindbrain. (B) (a) In the spinal cord, two types of progenitors (1 and 2) first generate neurons then glia. One progenitor type generates V2 interneurons (V2) and then astrocytes (a) and the other generates motoneurons (MN) and then oligodendrocytes (o). The lineage-specific factors Scl and Olig2, acting in combination with the temporal factor Sox9, influence whether an astrocytic or an oligodendrocytic cell identity is specified. (b) Loss of Sox9 activity in either progenitor type appears to prevent the neuronal-to-glial switch. (c) The orphan nuclear receptors Coup-TFI/II are transiently expressed in early neural progenitors and appear to act as switching factors as their knockdown prevents the switch from neurons (n) to glia (g). (C)(a) Cortical progenitors (large circles) can sequentially generate different neuronal subtypes (small coloured circles) during mouse embryogenesis that are each associated with different layers (SP, VI, V or IV/III/II). Fezf2 (Fzf2) is expressed in progenitors at the time they generate neurons that colonise layers VI and V. (b) Misexpression (red text) of Fezf2 during late stages of corticogenesis forces late progenitors to generate Ctip2+ neurons (yellow) typical of layer V. Fezf2 inactivation results in an excess of Satb2+ neurons (green), typical of superficial layers IV/III/II, at the expense of layer VI and V neurons.

View larger version (27K): [in this window] [in a new window]   Fig. 4. Model for an asymmetrically dividing multipotent progenitor. A single multipotent progenitor (large oval) is shown at several different time points during development. The progenitor divides asymmetrically to `self renew' and to generate a sequence of postmitotic progeny (small ovals), each with a different temporal identity (represented by the different colours). Within the progenitor, a temporal series timer (crescent) regulates the activity of switching factors with time and thus the frequency of the transitions (indicated by a sweeping arrow) between different progenitor TTFs (A B C D E). The core of the temporal series timer would be progenitor-intrinsic and could include both oscillatory and hourglass-like elements (reviewed by Pourquie, 1998; Rensing et al., 2001). Cross-regulatory repressions between some progenitor TTFs can promote these transitions (lines above letters indicate a selection of possible interactions), which may occur after one or many intervening cell cycles. Transient expression of progenitor TTFs can induce long-lasting changes in the expression pattern of a set of target genes - the progenitor competence factors. These, in turn, can modify several properties of the progenitors, including their ability to respond to later progenitor TTFs in the sequence. Progenitor TTFs also function, in combination with progenitor competence factors, to regulate the postmitotic TTFs (1, 2, 3, 4 and 5) that define the temporal identity of postmitotic progeny. Temporal identities can be stabilised by cross-regulatory interactions between the postmitotic TTFs (lines between numbers indicate a selection of possible repressions). Possible mechanisms for transmitting and transducing progenitor temporal information into the temporal identity of postmitotic daughter cells are discussed in the main text. For clarity, only one linear progenitor sequence (branch) is shown and intermediate progenitors are omitted. However, the main features of this general model also apply to progenitor lineages with more than one branch, such as those in the cerebral cortex and haematopoietic system.

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