The post-transcriptional regulation of TFs in immature motoneurons shapes the axon-muscle connectome
Authors: WENYUE GUAN 1; Stéphanie Bellemin 1; Mathilde Bouchet 1; Lalanti Venkatasubramanian 2; Camille Guillermin 1; Anne Laurençon 1; Kabir Chérif 1; Aurélien Darnas 1; Christophe Godin 3; Séverine Urdy 1; Richard S. Mann 2; Jonathan Enriquez 1
Affiliations: 1) Institut de génomique fonctionnelle de Lyon, ENS de Lyon; 2) Mortimer B. Zuckerman Mind Brain Behavior Institute, Columbia University; 3) Laboratoire Reproduction et Développement des Plantes, Univ Lyon, ENS de Lyon
Keywords: d. neuronal specification; p. RNA binding proteins
Temporal factors expressed sequentially in neural stem cells, such as RNA binding proteins (RBPs) or transcription factors (TFs), are key elements in the generation of neuronal diversity. The molecular mechanism underlying how the temporal identity of stem cells is decoded into their progeny to generate neuronal diversity is largely unknown. Here, we used genetic manipulations and a new computational tool to study the unique fates of the progeny of a stem cell producing 29 morphologically distinct leg motoneurons (MNs) in Drosophila. We identified 19 combinatorial codes of transcription factors (TFs) expressed in immature MNs (iMNs) just before their morphological differentiation. Importantly these TF codes are progressively established as a function of their birth date. The comparison of the RNA and protein expression patterns of 6 TFs in the 29 iMNs in different combinations revealed that post-transcriptional regulation plays an essential role in shaping these TF codes. We found that the two known RBPs, Imp and Syp, temporally expressed in the NB and maintained in iMNs according to their birth date, are key players in the construction of the axon-muscle connectome. Both RBPs post-transcriptionally regulate 5 of the 6 TFs examined, which in turn control the establishment of the axon muscle-connectome. By deciphering the function of Imp in the iMNs with respect to the stem cell, we propose a model whereby these two crucial RBPs act in iMNs to specify the unique morphological fate of individual MNs. Taken together, our study reveals that iMNs have the potential to acquire different morphological fates because of a broad expression of different TF mRNAs. However, these potentials are post-transcriptionally narrowed down to single iMN or subpopulations of iMNs by Imp and Syp, and potentially by other RBPs that remain to be discovered, to ultimately fine-tune the morphological fates of individual MNs.