Common Temporal Identity Factors Regulate Neuronal ...

1 Neuron Previews Common Temporal Identity Factors Regulate Neuronal diversity in Fly Ventral Nerve Cord and Mouse Retina Nikolaos Konstantinides,1 Anthony M. Rossi,1 and Claude Desplan1,*. 1 Department of Biology, new york university , 1009 Silver Center, 100 Washington Square East, New york , NY 10003, USA. *Correspondence: Temporal sequences of transcription Factors (tTFs) in Drosophila neural progenitors generate Neuronal diver- sity. Mattar et al. (2015) identify Casz1/Castor as a late Temporal Identity factor in mouse retinal progenitors that is regulated by the early factor Ikzf1/Hunchback, thus generalizing the notion of tTFs.

2 The nervous system consists of diverse tTF sequences have been identified in amacrine cells. Rods are produced in a neurons organized into complex circuits. neuroblasts: Homothorax, Klumpfuss, second wave of neurogenesis, while bipo- A goal of developmental neurobiology is Eyeless, Sloppy-paired, Dichaete, and lar and Mu ller glial cells are the last cell to understand the molecular mechanisms Tailless in the center of the outer prolifer- types to be born. The different cells are that guide neurogenesis. It is well estab- ation center (Li et al., 2013) and Distalless, produced within specific time windows lished that spatial positioning of neural Eyeless, Sloppy-paired, and Dichaete in that overlap extensively (Young, 1985.)

3 Progenitors contributes to the production the tips of the outer proliferation center Cepko, 2014). Ikzf1 is necessary and suf- of unique neural fates. In addition, studies (Bertet et al., 2014). Intermediate neural ficient for the generation of all early-born of neurogenesis in different species reveal progenitors (INPs), which are also present retinal cell types apart from cones that specific neurons are born in an in the subventricular zone of the adult (Figure 1A) (Elliott et al., 2008). However, invariant order ( Temporal patterning; for mammalian brain (Doetsch et al., 1999), one gene is far from a Temporal series, review, see Cepko, 2014).

4 For example, expand Drosophila neuroblasts lineages and no other reports of tTF genes in neural neurons in the vertebrate cortex are by progressing through a different tTF precursors have been published since. sequentially born in an inside-out fashion cascade (Dichaete, Grainyhead, and Mattar et al. (2015) studied the expres- to populate the six cortical layers. Other Eyeless) that is overlaid onto the Temporal sion pattern of Casz1, the ortholog of examples of Temporal patterning have progression of parental neuroblasts Castor, during mouse retinal develop- been described in vertebrates and inver- (Bayraktar and Doe, 2013).

5 These studies ment. They discovered that Casz1 is ex- tebrates. This suggests that birth-order suggest that different tTF sequences are pressed in RPCs at mid-retinogenesis is a second axis of information, which, used by multiple neural progenitors in a (Figure 1A). Conditional deletion of Casz1. coupled with spatial position, confers context-dependent manner to intrinsically in RPCs increases early-born cell types specific cell fates. determine age (Figure 1B). The parallels as well as Mu ller glia, the latest cell type How are neurons born sequentially? An shared between Drosophila and verte- produced by RPCs. Furthermore, retro- interesting model first described in the brate neural progenitors, particularly the viral transfection of Casz1 in early RPCs re- Drosophila embryonic ventral nerve cord sequential birth of Neuronal types, hint duces early-born neurons and late-born (VNC) is that neural progenitors, termed that the molecular mechanisms may be Mu ller glia, while concurrently increasing neuroblasts, sequentially express a series similar.

6 However, Temporal patterning of mid-phase bipolar cells and rods. In both of Temporal Transcription Factors '' (tTF) Neuronal progenitors by tTFs has not cases, no effect on clone size is observed. as they age. Once provided with spatial been described in vertebrates. These results suggest that Casz1 sup- patterning cues, each neuroblast pro- The only indication of Temporal presses early and late cell fates, and pro- gresses through the tTF sequence to pro- patterning in vertebrates comes from the motes the production of rods and bipolar duce lineage-specific Neuronal types in an observation that a mouse homolog of cells, without affecting proliferation or cell invariant order (Brody and Odenwald, Hunchback, Ikzf1, is expressed in early death.)

7 Interestingly, a division of labor ex- 2000; Isshiki et al., 2001). retinal progenitor cells (RPCs) (Elliott ists in the production of mid-phase neu- In the fly VNC, Hunchback, Kru ppel, et al., 2008). RPCs produce all Neuronal rons between the two isoforms of Casz1, Pdm, Castor, and Grainyhead are retinal cells, as well as glia: input sensory although their expression pattern seems sequentially expressed in neuroblasts as neurons (cone and rod photoreceptors), identical; Casz1v1 increases the number they age (Brody and Odenwald, 2000; interneurons (horizontal, bipolar, and of bipolar cells, while Casz1v2 produces Pearson and Doe, 2003).

8 During each amacrine cells), output neurons (retinal extra rods. These results are consistent tTF time window, neuroblasts generate ganglion cells), and Mu ller glial cells. The with the hypothesis that Casz1 is a tempo- specific subsets of VNC neurons. In the first cells to be born are retinal ganglion ral Identity factor defining the mid-stage of developing fly optic lobes, two related cells, then horizontal cells, cones, and RPCs (Figure 1A). Neuron 85, February 4, 2015 2015 Elsevier Inc. 447. Neuron Previews Hunchback and Castor, the flies and mice to distinguish fly homologs of Ikzf1 and different age states. Potential Casz1, participate in a tTF participation of other members sequence during Drosophila of the Drosophila Temporal embryonic VNC develop- sequence in the RPC Temporal ment.

9 Hunchback represses sequence would support this Castor expression in young hypothesis. For example, in neuroblasts and promotes Drosophila VNC neuroblasts, early-born cell fates (Tran the tTF sequence recapitulates et al., 2010). Similarly, Mattar the spatial expression of the et al. (2015) show that Ikzf1 same genes along the antero- lies upstream and acts as a posterior axis of the fly cellular repressor of Casz1. However, blastoderm embryo (Figure 1B). Ikzf1 repression of Casz1 is (Isshiki et al., 2001). This hints achieved indirectly, as Ikzf1 toward the presence of a com- does not bind Casz1 cis-reg- mon gene regulatory network ulatory elements, perhaps that operates in both space indicating the existence of and time.

10 An intermediate tTF between (b) Alternatively, the Hunch- Ikzf1 and Casz1 (Figure 1B). back-Castor and Ikzf1-Casz1. The fact that the Ikzf1-Casz1 regulatory modules might regulatory logic appears to have been assembled inde- be conserved in the mouse pendently. There is a re- retina and fly VNC raises an stricted number of transcrip- exciting question of evolu- tion Factors that can be used tionary significance: is this to orchestrate specific neu- an example of deep homol- ronal Identity and morpholog- ogy, or is it a mechanism ical characters, which could reached independently in the explain why the same tran- two cases driven by chance scription Factors are used at and necessity?