title: 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.
authors.affiliation: Division of Molecular Genetics, Department of Physics, Chemistry and Biology, Linkoping University, Linkoping, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Baumgardt
authors.forename: Irene
authors.initials: I
authors.lastname: Miguel-Aliaga
authors.forename: Daniel
authors.initials: D
authors.lastname: Karlsson
authors.forename: Helen
authors.initials: H
authors.lastname: Ekman
authors.forename: Stefan
authors.initials: S
authors.lastname: Thor
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D004330:Drosophila / Q000166:cytology* / Q000196:embryology* / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D019835:FMRFamide / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins / Q000378:metabolism; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology
chemical_list: C093147:Dop1R1 protein, Drosophila; D029721:Drosophila Proteins; D005136:Eye Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D008565:Membrane Proteins; D009479:Neuropeptides; C518480:Nplp1 protein, Drosophila; D011954:Receptors, Dopamine; D014157:Transcription Factors; C074459:ap protein, Drosophila; C092694:eya protein, Drosophila; C104357:kn protein, Drosophila; D019835:FMRFamide