a prevailing model explaining cell fate specification during central nervous system ( cns ) development is the  combinatorial code , in which cell identity is determined by the expression of specific combinations of transcription factors ( tfs ) . tf codes controlling cell fate during neurogenesis are indeed well established in many cns regions , such as the drosophila ventral nerve cord or vertebrate spinal cord . in these systems , neural progenitors interpret morphogen gradients to acquire distinct tf signatures based on their position in space . these tf combinations act as a code to endow progenitors with the potential to give rise to the appropriate neuronal subtypes . particularly prominent are homeodomain tfs from the hox and extended hox families , as well as bhlh tfs of the proneural he s and olig families . while tf combinations represent a powerful and elegant framework for explaining cell fate decisions during cns development , it has proven to be difficult to decode the most complicated neural lineages . in regions such as the vertebrate neocortex and retina , multipotent progenitors of a given spatial domain alter their output over time to generate sequences of different types of neuronal and glial cells . in the retina , this sequence begins with the production of retinal ganglion cells , followed closely by the overlapping generation of cone photoreceptors , horizontal , and amacrine neurons . as the generation of these cell types peaks , rod photoreceptors begin to be produced . at birth , production of most of the early - born neuronal subtypes ceases , rod production continues , and bipolar neurons and latest - born mller glia begin to be generated in an overlapping fashion . in the neocortex and hindbrain , evidence suggests that both extrinsic factors , and cell - intrinsic processes are important to control the temporal identity of progenitors . in the developing retina , however , even though extrinsic signaling has been shown to alter progenitor output , these factors are thought to mostly control proliferation and act as negative feedback inhibition signals to refine the size of a specific neuronal population , rather than regulate temporal identity in retinal progenitors . instead , cell - intrinsic processes appear to play a dominant role to control progenitor fate output , both when retinal progenitors were cultured in heterochronic transplants or cell pellets , or when cultured individually . retinal progenitors can not maintain the same combinatorial tf code during retinogenesis , or their output would be static . yet , identification of the key tfs that define the competence state of retinal progenitors at specific phases of development has remained largely elusive . while a great deal of progress has been made in identifying tfs that contribute to the generation of particular cell fates during retinal development , many of these factors , such as lhx2 , pax6 , rx , and vsx2 are expressed in retinal progenitors throughout development and therefore can not explain on their own the sequential order of cell birth . conversely , fate determinants such as ascl1 , atoh7 , olig2 , onecut1/2 , otx2 , prdm1 ( blimp-1 ) , and sox4/11 exhibit dynamic patterns temporally , but in each case , data suggests that these factors act at the last or penultimate cell division rather than in bona fide multipotent progenitors . thus , although the collective efforts of a large number of laboratories have identified many tfs that contribute to the combinatorial coding of each retinal cell type , we have little understanding of how multipotent vertebrate retinal progenitors select between them to generate lineages of the appropriate size and complexity . in contrast , in drosophila , the mechanism controlling temporal competence during development has been well characterized . in neuroblasts of the ventral nerve cord or medulla , additional tf cascades operate in time , acting to diversify the tf code established spatially by the actions of morphogens . in the fly ventral nerve cord , landmark work had shown that most neuroblasts express a sequence of tfs as development proceeds : hunchback , krppel , nub / pdm2 ( collectively pdm ) , and castor ( fig . these tfs are necessary and sufficient to confer temporal identity to neuroblasts , such that they produce daughter cell types in the correct sequence . ( a ) roles of the temporal tfs hunchback ( hb ) and castor ( cas ) in the sequential generation of cell fates during development of the drosophila neuroblast nb71 motoneuron lineage . ( b ) analogous roles of the murine hb and cas orthologues ikzf1 and casz1 in regulating the temporal competence of retinal progenitors . casz1 might function by suppressing the competence of genes to be expressed rather than by directly controlling target gene levels . elucidation of the co - factor complexes utilized by casz1 should allow this hypothesis to be addressed . this model is not meant to be exclusive , and alternative factors not shown here could be involved . ( a ) roles of the temporal tfs hunchback ( hb ) and castor ( cas ) in the sequential generation of cell fates during development of the drosophila neuroblast nb71 motoneuron lineage . ( b ) analogous roles of the murine hb and cas orthologues ikzf1 and casz1 in regulating the temporal competence of retinal progenitors . casz1 might function by suppressing the competence of genes to be expressed rather than by directly controlling target gene levels . elucidation of the co - factor complexes utilized by casz1 should allow this hypothesis to be addressed . this model is not meant to be exclusive , and alternative factors not shown here could be involved . previously , we had shown that the zinc finger tf ikzf1 ( ikaros ) , an ortholog of drosophila hunchback , was sufficient to impart late retinal progenitors with the competence to generate early - born neuronal subtypes , as well as being required for the generation of normal numbers of early - born fates during development . because ikzf1 had no effect on retinal progenitor proliferation , these results indicated that ikzf1 does not control the timing of cell cycle exit , but instead directly confers early temporal identity in retinal progenitors , which are biased to give rise to early - born neurons when they express ikzf1 ( fig . interestingly , recent work showed that ikzf1 misexpression in cortical progenitors resulted in prolonged period of production of early - born neurons well into the late temporal identity window . although ikzf1 was not absolutely required for early - born neuronal cell type production in the developing cortex , these results suggest that ikzf1 could be a general factor regulating early temporal identity in vertebrates , much like hunchback is essential to control early temporal identity in multiple fly neuroblast lineages . while ikzf1 and hunchback appear to function analogously , it remained unclear how ikzf1 achieved these effects in the retina . whereas drosophila hunchback operates within the context of a tf cascade that changes over time , indeed , a single homolog of the drosophila zinc finger tf castor , called casz1 , was previously shown to be expressed in later phases of retinogenesis , as well as in differentiated photoreceptors . we therefore hypothesized that an ikzf1  casz1 sequence might represent conservation of the drosophila temporal code . to test this hypothesis , we recently used mouse genetics and retroviral lineage tracing to study casz1 function during retinogenesis . we showed that casz1 is not expressed at significant levels at early stages , but is upregulated in retinal progenitors during mid / late stages of retinal development , suggesting a role in controlling temporal identity at these later stages ( fig . consistently , we found that precocious misexpression of casz1 in retinal progenitors was sufficient to increase the production of mid / late fates like bipolar cells and rod photoreceptors , at the expense of early fates such as cone photoreceptors , horizontal cells , and amacrine cells . conversely , analysis of retinal progenitor cell lineages in conditional casz1 knockout retinas showed increased production of early - born fates at the expense of rod photoreceptors within a lineage . importantly , similar to what was observed with ikzf1 , the cell fate changes observed following casz1 manipulations were independent of an effect on proliferation or cell death , indicating that casz1 directly controls temporal identity in retinal progenitors and not cell cycle exit . interestingly , we also found that ikzf1 normally represses casz1 expression in retinal progenitors , and identified the cis - regulatory modules in casz1 that can mediate the transcriptional effects of ikzf1 . together these results suggest that , much like in drosophila neuroblasts , a cross - regulatory mechanism of tf expression operate to control temporal identity progression in mouse retinal progenitor cells . although the biochemical activities underlying casz1 function have been studied to some extent in the developing heart , muscle and vascular systems , where casz1 is thought to control progenitor proliferation and differentiation , the mechanism by which casz1 confers temporal identity in neural progenitors remains unknown . in drosophila neuroblasts , cas was initially suggested to function as a transcriptional repressor , but a mechanistic understanding of its activities remains incomplete . in an effort to provide some clues about casz1 mechanism of action , we recently carried out a gene expression profiling experiment using rna - seq on casz1 knockout retinal progenitors . however , this approach failed to identify strong effects on cell fate determinants that could explain casz1 function ( mattar and cayouette , unpublished data ) . although changes were observed in the levels of transcripts for genes that are known to control the production of cell types affected by casz1 conditional deletion , the changes observed were no larger than 5-fold for any of them . these results suggest that casz1 might not directly modify the combinatorial tf code , but instead could function by mediating more subtle epigenetic changes . indeed , castor proteins have recently been shown to associate with a variety of transcriptional regulators , including the mi-2/nurd and polycomb repressor complexes . intriguingly , previous work has shown that mi-2/nurd is required for ikzf1-mediated fate determination functions in lymphocytic development . similarly , in fly neuroblasts and mouse cortical or retinal progenitors , polycomb repressive complexes have been shown to regulate temporal identity , suggesting that temporal tfs might regulate competence via common epigenetic pathways . in such a model , casz1 could act by altering the probability and/or competence of specific fate determination genes to be transcribed , rather than acting as a straightforward modifier of tf expression levels ( fig . consistent with this hypothesis , changes in the temporal competence of drosophila neuroblasts are controlled by alterations in the competence of fate determinant genes to be expressed . whether casz1 could function together with mi-2/nurd and/or polycomb to provide target gene specificity for chromatin modifications remains unknown , but this is certainly an interesting possibility . other potential explanations for the effects of ikzf1/casz1 on progenitor competence are of course possible , based on the identification of factors that have also been shown to regulate progenitor temporal identity or progression . in xenopus laevis , dicer , a key determinant of microrna biosynthesis and function , was shown to control the correct onset of markers of late - born cell types , and several micrornas were implicated in this effect . subsequently , a role for dicer and the micrornas let7 , mir9 , and mir125 in the progression of retinal progenitor temporal identity from early- to late - phase was uncovered . these effects may be mediated in part by protogenin and lin28 , which were shown to be targets of the micrornas . moreover , the requirement for dicer / micrornas in the progression of temporal competence states is very similar to that of lhx2 , which when mutated , stalls retinal progenitors in the earliest phase of neurogenesis . whether there are mechanistic connections between ikzf1/casz1 , dicer / micrornas , and lhx2 remains unclear , but in c. elegans , the hunchback ortholog hbl-1 and the let-7 microrna cross - regulate each other , with hbl-1 repressing let-7 expression , and let-7 binding and inhibiting the hbl-1 3 ' utr . if conservation of this negative feedback loop is maintained in the retina , this might suggest a possible point of convergence for these pathways . alternatively , these pathways might act independently , providing redundancy and robustness to the system . elucidating how temporal identity factors function in vertebrate neural progenitors to control the production of specific cell types associated with a given developmental window will be important , as this knowledge could provide novel ways of manipulating stem cell differentiation for cell replacement therapies . a recent study , for example , reported that tgf functions as a regulator of temporal identity in hindbrain progenitors and provided proof of concept that manipulating tgf can be applied to control temporal specification of specific neuronal types from stem cells . this work was supported by research grants from the foundation for fighting blindness canada , and the canadian institutes of health research ( mop-77570 ) . pm was supported by a cihr postdoctoral fellowship , and mc is a senior fellow of the fond de la recherche du qubec