Conserved gene regulatory module specifies lateral neural borders across bilaterians

Abstract

The lateral neural plate border (NPB), the neural part of the vertebrate neural border, is composed of central nervous system (CNS) progenitors and peripheral nervous system (PNS) progenitors. In invertebrates, PNS progenitors are also juxtaposed to the lateral boundary of the CNS. Whether there are conserved molecular mechanisms determining vertebrate and invertebrate lateral neural borders remains unclear. Using single-cell-resolution gene-expression profiling and genetic analysis, we present evidence that orthologs of the NPB specification module specify the invertebrate lateral neural border, which is composed of CNS and PNS progenitors. First, like in vertebrates, the conserved neuroectoderm lateral border specifier Msx/vab-15 specifies lateral neuroblasts in Caenorhabditis elegans. Second, orthologs of the vertebrate NPB specification module (Msx/vab-15, Pax3/7/pax-3, and Zic/ref-2) are significantly enriched in worm lateral neuroblasts. In addition, like in other bilaterians, the expression domain of Msx/vab-15 is more lateral than those of Pax3/7/pax-3 and Zic/ref-2 in C. elegans. Third, we show that Msx/vab-15 regulates the development of mechanosensory neurons derived from lateral neural progenitors in multiple invertebrate species, including C. elegans, Drosophila melanogaster, and Ciona intestinalis. We also identify a novel lateral neural border specifier, ZNF703/tlp-1, which functions synergistically with Msx/vab-15 in both C. elegans and Xenopus laevis. These data suggest a common origin of the molecular mechanism specifying lateral neural borders across bilaterians.C. elegans | neural plate border | neural border | Msx/vab-15 | ZNF703/tlp-1 T he vertebrate neural border is a transient embryonic domain located between the neural plate and nonneurogenic ectoderm from late gastrulation to early neurulation. The neural border is composed of the lateral neural plate border (NPB) and preplacode ectoderm (PPE) subdomains (1, 2). The NPB and PPE give rise to the neural crest and placode, respectively, both of which undergo epithelial-to-mesenchymal transition/delamination, migrate in prototypical paths, and give rise to the peripheral nervous system (PNS) and many other cell types (3, 4). However, the NPB and PPE also have many different features (5). For example, the PPE is confined to the anterior half of embryos and does not contribute to the central nervous system (CNS), whereas the NPB is the lateral border of the whole neural plate and consists not only of progenitors for the PNS but also those for the CNS in the dorsal neural tube. The juxtaposed localization of the CNS neuroectoderm and PNS progenitors also occurs in the trunk of invertebrate embryos such as nematodes, arthropods, annelids, and urochordates (6-9), reminiscent of vertebrate NPB. In Caenorhabditis elegans, lateral neuroblasts (P, Q, and V5 cells) are located between the embryonic CNS and skin from the birth of these cells (10). In addition, worm lateral neuroblasts possess several key cellular and developmental features of vertebra...

Lateral neural borders as precursors of peripheral nervous systems: A comparative view across bilaterians

“…Q neuroblasts in Msx / vab‐15 mutants show a defect in migration too, and fail to give rise to mechanosensory neurons with nearly full penetrance. Similarly, V5 neuroblasts in Msx / vab‐15 mutants also fail to give rise to neurons (Li et al., ).…”

“…So, like vertebrate NPB, the Ciona counterpart give rise to both migratory and non‐migratory PNS neurons. Furthermore, Ciona NPB also expresses orthologs of vertebrate “neural‐plate‐border module,” including Msx , Zic and Pax3 / 7 and juxtapose with Dlx ‐expressing non‐neurogenic ectoderm, and Msx also plays a critical role in the specification of NPB in Ciona , as it is in vertebrates (Li et al., ; Roure & Darras, ; Stolfi et al., ; Waki et al., ). At last, Ciona NPB cell lineage expresses some critical features of vertebrate NBP derivatives: neural crest and placode.…”

“…But in Msx / msh mutants, the chordotonal organs contained fewer neurons and glial cells. Furthermore, the migration of the progeny cells derived from the SOPs in mutant embryos appeared to be significantly desynchronized (Li et al., ). In short, Msx / msh plays a minor, but significant role in the development of lateral PNS neuroblasts.…”

“…At the molecular level, orthologs of vertebrate NPB specifiers Msx / vab‐15 , Pax3 / 7 / pax‐3 and Zic / ref‐2 are specifically expressed and play important roles in worm lateral neuroblasts. Specifically, activity of Pax3 / 7 / pax‐3 and Zic / ref‐2 is limited in CNS progenitor P neuroblasts while Msx / vab‐15 is active in both P and PNS progenitor Q and V5 neuroblasts (Li et al., ). For example, P neuroblasts in Msx / vab‐15 mutants are significantly defective in nuclear migration, and those that migrate into the ventral midline frequently fail to give rise to hypodermal daughter cells or neurons.…”

“…After the division of V5/Q mother cell, Msx / vab‐15 expression maintains only in Q cell and plays an important role in cell migration of Q descendants (Li et al., ). At last, Msx / vab‐15 functions synergistically with ZNF703 / tlp‐1 to regulate cell fate both in worm lateral neuroblasts and in Xenopus NPB (Hong & Saint‐Jeannet, ; Li et al., ). These data suggest that the ancestor of nematode and chordates had lateral neural border as a developmental domain that was located lateral to CNS, specified by Msx and other core components of NPB specification module and produced neurons in PNS.…”