Neuronal Regulation of the Spatial Patterning of Neurogenesis

Abstract

Summary Precise regulation of neurogenesis is achieved in specific regions of the vertebrate nervous system by formation of distinct neurogenic and non-neurogenic zones. We have investigated how neurogenesis becomes confined to zones adjacent to rhombomere boundaries in the zebrafish hindbrain. The non-neurogenic zone at segment centres comprises a distinct progenitor population that expresses fgfr2, erm, sox9b and the retinoic acid degrading enzyme cyp26b1. FGF receptor activation upregulates expression of these genes and inhibits neurogenesis in segment centres. Cyp26 activity is a key effector inhibiting neuronal differentiation, suggesting antagonistic interactions with retinoid signaling. We identify the critical FGF ligand, fgf20a, which is expressed by specific neurons located in the mantle region at the centre of segments, adjacent to the non-neurogenic zone. Fgf20a mutants have ectopic neurogenesis and lack the segment centre progenitor population. Our findings reveal how signaling from neurons induces formation of a non-neurogenic zone of neural progenitors.

Opposing actions of histone deacetylase 1 and Notch signalling restrict expression of erm and fgf20a to hindbrain rhombomere centres during zebrafish neurogenesis

“…Expression of erm in the hindbrain ventricular zone is strictly dependent on fgf20a function in a subset of neurones within the underlying mantle region (Gonzalez-Quevedo et al, 2010). We therefore sought to determine whether, as for erm, the expression pattern of fgf20a in the hindbrain is influenced by Hdac1 function and Notch signalling.…”

“…We wondered whether Hdac1 might therefore regulate expression of genes involved in neuronal patterning within rhombomeres, such as the transcription factor gene erm, fgf20a-dependent transcription of which is restricted to a series of robust stripes that are located at rhombomere centres (Roussigné and Blader, 2006;Gonzalez-Quevedo et al, 2010). We addressed this question by first analysing expression of erm in wild-type and hdac1 mutant embryos at 21, 24 and 31 hours post-fertilisation (hpf), which correspond to developmental time points shortly before and after the morphological phenotype of hdac1 mutant embryos first becomes apparent (Cunliffe, 2004).…”

“…Some of the crucial steps underlying lineage restriction and the commitment of neural progenitors to specific differentiated neuronal or myelinating glial fates include progenitor withdrawal from the cell cycle, transcriptional silencing of neural progenitor determinants and transcriptional activation of genes encoding bHLH transcription factors such as ascl1b, neurog1 (Bertrand et al, 2002) and olig2 (Rowitch, 2004). However, the processes driving commitment of proliferating progenitors to neuronal and glial fates in the CNS are countered by the regulated expression of neural progenitor maintenance factors such as the SoxB1 proteins (Pevny and Placzek, 2005) as well as the regulated activity of the Wnt, Notch and FGF signalling pathways (Ille and Sommer, 2005;Louvi and ArtavanisTsakonas, 2006;Gonzalez-Quevedo et al, 2010), which provide negative feedback that limits the rate and pattern of neurogenesis.…”

“…Accumulating evidence suggests that FGF-regulated transcription factors, such as the ETS-domain proteins Erm, Pea3 and Etv5, play important roles in neural specification and/or patterning within the developing CNS (Gonzalez-Quevedo et al, 2010;Raible and Brand, 2001;Roussigné and Blader, 2006). In the hindbrain, transcripts encoding Erm and its positive regulator Fgf20a are restricted to stripes of tissue within rhombomeres (Roussigné and Blader, 2006;Gonzalez-Quevedo et al, 2010), and recent work suggests that Erm could function in the establishment of Fgf20a-dependent, non-neurogenic zones at rhombomere centres (Gonzalez-Quevedo et al, 2010).…”

“…In the hindbrain, transcripts encoding Erm and its positive regulator Fgf20a are restricted to stripes of tissue within rhombomeres (Roussigné and Blader, 2006;Gonzalez-Quevedo et al, 2010), and recent work suggests that Erm could function in the establishment of Fgf20a-dependent, non-neurogenic zones at rhombomere centres (Gonzalez-Quevedo et al, 2010). Here, we demonstrate opposing roles for Hdac1 and Notch pathway signalling activity in regulating expression of both erm and fgf20a in the zebrafish hindbrain, which further suggests crucial functions for this transcription factor and its upstream signal in regulation of neurogenesis.…”