Organs are the functional units of multicellular organisms. For proper organ function not only the correct cell types need to be specified, they must also be arranged in a specific shape. Hence both, cell type specification and morphogenesis need to be tightly controlled and coordinated to guarantee proper organ formation and function. In the present preprint, the authors use the olfactory epithelium of zebrafish to investigate the mechanisms that link these processes during development. The olfactory epithelium is a sensory system used to detect odors. It is derived from the olfactory placode, which is specified adjacent to the anterior neural plate . Neurogenesis happens in two consecutive waves that depend on the proneural transcription factors Neurog1 and Neurod4 . Concomitant with the first wave of neurogenesis, morphogenetic movements lead to the formation of the olfactory placode . Morphogenesis is largely driven by chemokine signalling via the receptor Cxcr4b and its ligand Cxcl12a . The present preprint tackles the question of how neurogenesis, driven by Neurog1, and morphogenesis, driven by chemokine signalling, are coordinated. The authors find that Neurog1 is not only an important component in neurogenesis , but also a regulator of morphogenesis by directly regulating cxcr4b transcription.
Proneural transcription factor Neurog1 affects olfactory placode morphogenesis
Analysis of homozygous neurog1hi1059 mutants  revealed morphogenetic defects in olfactory placode formation during the development of the olfactory epithelium. These defects manifest in a developmental delay in cellular convergence, leading to a transiently increased AP (anterior-posterior) length of the EON (early-born olfactory neurons) population compared to wild type. To investigate the defect in more detail, the authors injected H2B-RFP mRNA (leads to a nuclear label) into the neurog1 mutant background and tracked movements of single Neurog1 positive EON by time-lapse imaging from 12 to 27 hours post fertilization. This revealed that only a subset of EON positioned in the anterior third of the Neurog1 population displayed a morphogenetic defect, whereas EON from the middle or posterior third behaved similarly to wild type cells. These results suggest that Neurog1 not only regulates neurogenesis, but also impacts on morphogenesis in a subpopulation of EON in the olfactory system.
Neurog1 induces cxcr4b expression
Chemokine signalling via Cxcr4b and Cxcl12a is crucial for the morphogenetic movements leading to olfactory placode formation . Following the same rationale as before, the authors analysed the behaviour of EON in cxcr4bt26035  and cxcl12at20516  mutants. Similar to neurog1hi1059 mutants, an increased AP length of the placode caused by defects in the migratory behaviour of anterior EON could be observed. To examine a possible link between Neurog1 and Cxcr4b/Cxcl12a, analysis of cxcr4b and cxcl12a expression was performed via in situ hybridisation in the neurog1hi1059 mutant background. Expression of cxcl12a was unaltered, whereas cxcr4b expression was reduced from 12 to 15 hours post fertilization, the time window when the morphogenetic defect occurs. Around 18 hours post fertilization, cxcr4b expression was restored, most likely due to a compensatory effect exerted by Neurod4, another proneural transcription factor. From this, the authors hypothesised that the morphogenetic defect observed in neurog1hi1059 mutants was due to a lack of Cxcr4b. To test this hypothesis, a rescue experiment was performed, where cxcr4b was expressed in the Neurog1 population in neurog1hi1059 mutants. Analysis of migratory behaviour of EON in neurog1hi1059 mutant fish carrying the transgene did not reveal any morphogenetic defects. Therefore, the authors concluded that Cxcr4b is a downstream effector of Neurog1 during the formation of the olfactory placode.
Cxcr4b is a direct transcriptional target of Neurog1
To further investigate the link between Neurog1 and Cxcr4b, the authors looked for known proneural transcription factor binding sites (E-boxes) in the cxcr4b locus and identified one possible candidate site for Neurog1 binding. A 35kb fosmid clone containing this CAGATG cluster was able to drive GFP expression in the Neurog1 cell population (TgFOS(cxcr4b:eGFP)). To confirm this cluster as a Neurog1 binding site, ChIP experiments were performed. And indeed, the CAGATG cluster in the cxcr4b locus could be identified as a Neurog1 binding site, indicating that Neurog1 directly controls cxcr4b on a transcriptional level. To validate the importance of this specific CAGATG cluster for cxcr4b expression, the Crispr system was used to specifically mutate the cluster in the TgFOS(cxcr4b:eGFP) reporter, resulting in a loss of GFP expression. Hence, Neurog1 controls morphogenesis via transcriptional activation of cxcr4b expression by binding to a specific CAGATG cluster in the cxcr4b locus.
Why I like this preprint
The individual processes of cell-type specification and morphogenesis have been well studied in a variety of organs. However, we are only beginning to understand how these processes are coordinated during development. In this preprint, the authors present a possibly conserved mechanism that links these processes during the development of the olfactory epithelium.
In neurog1hi1059, cxcr4bt26035 and cxcl12at20516 mutants a morphogenetic defect can be observed in the EON population. Anterior EON seem to be more affected than more posterior ones. Why are the anterior EON more affected?
Loss of the proneural transcription factor Neurog1 leads to morphogenetic defects. Is there a similar feedback of tissue architecture generated by morphogenetic events on cell type specification in the olfactory epithelium?
- Miyasaka, N., et al., Functional development of the olfactory system in zebrafish. Mech Dev, 2013. 130(6-8): p. 336-46.
- Madelaine, R., L. Garric, and P. Blader, Partially redundant proneural function reveals the importance of timing during zebrafish olfactory neurogenesis. Development, 2011. 138(21): p. 4753-62.
- Whitlock, K.E. and M. Westerfield, The olfactory placodes of the zebrafish form by convergence of cellular fields at the edge of the neural plate. Development, 2000. 127(17): p. 3645-53.
- Miyasaka, N., H. Knaut, and Y. Yoshihara, Cxcl12/Cxcr4 chemokine signaling is required for placode assembly and sensory axon pathfinding in the zebrafish olfactory system. Development, 2007. 134(13): p. 2459-68.
- Golling, G., et al., Insertional mutagenesis in zebrafish rapidly identifies genes essential for early vertebrate development. Nat Genet, 2002. 31(2): p. 135-40.
- Knaut, H., et al., A zebrafish homologue of the chemokine receptor Cxcr4 is a germ-cell guidance receptor. Nature, 2003. 421(6920): p. 279-82.
- Valentin, G., P. Haas, and D. Gilmour, The chemokine SDF1a coordinates tissue migration through the spatially restricted activation of Cxcr7 and Cxcr4b. Curr Biol, 2007. 17(12): p. 1026-31.
Posted on: 5 May 2020Read preprint
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