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The Lin28/let-7 pathway regulates the mammalian caudal body axis elongation program

ABSTRACT: The heterochronic genes Lin28a/b and let-7 are well-established regulators of invertebrate development, however their functions in patterning the mammalian body plan remain unexplored. In this study, we discovered a novel function of Lin28/let-7 in controlling caudal vertebrae number during body axis formation. We found that FoxD1-driven overexpression of Lin28a or LIN28B led to a striking increase in caudal vertebrae number, whereas loss of Lin28a stunted tail formation. Accordingly, perturbation of the let-7 microRNA family led to the opposite phenotypes. We further show that overexpressing Lin28a in embryos resulted in increased tail bud cell proliferation, whereas Lin28a KO decreased cellular proliferation. This was accompanied by a transcriptional shift, including down-regulation of the neural marker Sox2, and resulted in a pro-mesodermal phenotype with decreased proportions of neural tissue relative to mesoderm in Lin28a-overexpressing embryos. Strikingly, Lin28a KO and let-7 over-expression demonstrated opposite effects, suggesting that the Lin28/let-7 pathway acts upstream of the signaling pathways controlling the self-renewal and cell fate commitment of neuro-mesodermal progenitors. We propose that Lin28a/b activity controls the pool of caudal progenitors during tail development, promotes their self-renewal potential, is involved in controlling the balance of neural versus mesodermal cell fate decisions, and that progressive down-regulation of Lin28a allows for species-specific vertebral formula to be achieved. These findings suggest that Lin28/let-7 play a role in the regulation of tail length through heterochrony of the body plan.

ORGANISM(S): Mus musculus

PROVIDER: GSE123193 | GEO | 2019/05/01

REPOSITORIES: GEO

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Project description:The spinal cord is generated progressively as cells leave the caudal region of the elongating body axis such that the temporal steps of neural differentiation become spatially separated along the head to tail axis. At key stages, it is therefore possible to isolate near-adjacent cell populations from the same embryo in distinct differentiation states. Cells in the caudal lateral epiblast adjacent to the primitive streak (also known as the stem zone, SZ, in the chick) express both early neural and mesodermal genes. Other cells in the stem zone will gastrulate to form the paraxial mesoderm or remain in the epiblast cell sheet and become neural progenitors. These latter cells form a new region called the preneural tube (PNT), which is flanked by unsegmented presomitic mesoderm and represents an early neural progenitor state that can be induced by FGF signalling to revert back to a multi-potent SZ state. Rostral to this, the closed caudal neural tube (CNT) is flanked by somites and is an early site of co-expression of genes characteristic of neural progenitors, and of ventral patterning genes (Diez del Corral et al., 2003). The CNT contains the first few neurons and exposure to FGF cannot revert this tissue to a multi-potent SZ state (Diez del Corral et al., 2002). The transition from the PNT to the CNT thus involves commitment to a neural fate that this is regulated by a switch from FGF to retinoid signalling. More advanced neuroepithelium is then located in more rostral neural tube (RNT), in which neuronal differentiation is ongoing and dorsoventral pattern is refined. This experiment uses the Affymetrix GeneChip chicken genome microarray to compare the transcriptomes of microdissections of these spatially distinct cell populations from the elongating neural axis of HH stage 10 chick embryos. Dissections were carried out in L15 medium at 4°C and explants pooled in TRIzol reagent (Gibco) for RNA extraction. Notochord was removed by controlled trypsin digestion that aimed to keep the neural ventral midline. For the microarrays, at least five tissue samples for each region were pooled to make each of three biological replicates for each (n>15 for each region).

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The Lin28/let-7 pathway regulates the mammalian caudal body axis elongation program

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