Specification of Neuronal Identities by Feedforward Combinatorial Coding

Abstract

Neuronal specification is often seen as a multistep process: earlier regulators confer broad neuronal identity and are followed by combinatorial codes specifying neuronal properties unique to specific subtypes. However, it is still unclear whether early regulators are re-deployed in subtype-specific combinatorial codes, and whether early patterning events act to restrict the developmental potential of postmitotic cells. Here, we use the differential peptidergic fate of two lineage-related peptidergic neurons in the Drosophila ventral nerve cord to show how, in a feedforward mechanism, earlier determinants become critical players in later combinatorial codes. Amongst the progeny of neuroblast 5–6 are two peptidergic neurons: one expresses FMRFamide and the other one expresses Nplp1 and the dopamine receptor DopR. We show the HLH gene collier functions at three different levels to progressively restrict neuronal identity in the 5–6 lineage. At the final step, collier is the critical combinatorial factor that differentiates two partially overlapping combinatorial codes that define FMRFamide versus Nplp1/DopR identity. Misexpression experiments reveal that both codes can activate neuropeptide gene expression in vast numbers of neurons. Despite their partially overlapping composition, we find that the codes are remarkably specific, with each code activating only the proper neuropeptide gene. These results indicate that a limited number of regulators may constitute a potent combinatorial code that dictates unique neuronal cell fate, and that such codes show a surprising disregard for many global instructive cues.

Quantitative expression profiling of identified neurons reveals cell-specific constraints on highly variable levels of gene expression

“…We argue that cell identity is not a static result of gene expression, but rather a continual balance between compensatory changes in gene expression and coordinated gene regulation that ensures robust output. Recent elegant studies have focused on complex gene networks as critical determinants of transcriptional regulation (30,31), but a relatively limited number of regulators may act in a combinatorial fashion to influence transcription and ultimately neuronal identity (32). Therefore, in mature neurons, a combinatorial code of coregulated ion channel expression may exist that acts as the primary determinant of the output of a cell at any given time.…”

“…Therefore, in mature neurons, a combinatorial code of coregulated ion channel expression may exist that acts as the primary determinant of the output of a cell at any given time. Baumgardt et al (32) suggest that the maintenance of this cellular output may require only a relatively few coordinating players acting in a combinatorial fashion, greatly reducing the complexity of feedback mechanisms (and the number of players involved) that would be required to coordinate channel expression in a cell-specific fashion to maintain appropriate neuronal output.…”

Transcription factor Olig2 defines subpopulations of retinal progenitor cells biased toward specific cell fates

“…The findings also provide evidence that some types of RPCs may behave as the ganglion mother cells (GMCs) of the Drosophila CNS, as GMCs also make terminal divisions that produce specific types of progeny, which change over time (23)(24)(25).…”

The EBF transcription factor Collier directly promotes Drosophila blood cell progenitor maintenance independently of the niche

“…To test this hypothesis, we inhibited Col expression specifically in the prohemocytes using a UAS-col dsRNA transgene whose expression was shown to reproduce col loss of function in different tissues (27,28). As shown in Fig.…”