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Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

ABSTRACT: We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor pool in the posterior lobule, which is not seen in other organisms, not even in the nonhuman primate the macaque. Disruptions in human rhombic lip development are associated with posterior cerebellar vermis hypoplasia and Dandy-Walker malformation. The presence of these species-specific neural progenitor populations refines our insight into human cerebellar developmental disorders.

SUBMITTER: Haldipur P

PROVIDER: S-EPMC6897295 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

Haldipur Parthiv P Aldinger Kimberly A KA Bernardo Silvia S Deng Mei M Timms Andrew E AE Overman Lynne M LM Winter Conrad C Lisgo Steven N SN Razavi Ferechte F Silvestri Evelina E Manganaro Lucia L Adle-Biassette Homa H Guimiot Fabien F Russo Rosa R Kidron Debora D Hof Patrick R PR Gerrelli Dianne D Lindsay Susan J SJ Dobyns William B WB Glass Ian A IA Alexandre Paula P Millen Kathleen J KJ

Science (New York, N.Y.) 20191017 6464

We present histological and molecular analyses of the developing human cerebellum from 30 days after conception to 9 months after birth. Differences in developmental patterns between humans and mice include spatiotemporal expansion of both ventricular and rhombic lip primary progenitor zones to include subventricular zones containing basal progenitors. The human rhombic lip persists longer through cerebellar development than in the mouse and undergoes morphological changes to form a progenitor p ...[more]

PMID: 31624095

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Project description:Understanding the mechanisms of controlled expansion and differentiation of basal progenitor cell populations during organogenesis is essential for developing targeted regenerative therapies. Since the cytokeratin 5-positive (K5+) basal epithelial cell population in the salivary gland is regulated by retinoic acid signaling, we interrogated how isoform-specific retinoic acid receptor (RAR) signaling impacts the K5+ cell population during salivary gland organogenesis to identify RAR isoform-specific mechanisms that could be exploited in future regenerative therapies. In this study, we utilized RAR isoform-specific inhibitors and agonists with murine submandibular salivary gland organ explants. We determined that RAR? and RAR? have opposing effects on K5+ cell cycle progression and cell distribution. RAR? negatively regulates K5+ cells in both whole organ explants and in isolated epithelial rudiments. In contrast, RAR? is necessary but not sufficient to positively maintain K5+ cells, as agonism of RAR? alone failed to significantly expand the population. Although retinoids are known to stimulate differentiation, K5 levels were not inversely correlated with differentiated ductal cytokeratins. Instead, RAR? agonism and RAR? inhibition, corresponding with reduced K5, resulted in premature lumenization, as marked by prominin-1. With lineage tracing, we demonstrated that K5+ cells have the capacity to become prominin-1+ cells. We conclude that RAR? and RAR? reciprocally control K5+ progenitor cells endogenously in the developing submandibular salivary epithelium, in a cell cycle-dependent manner, controlling lumenization independently of keratinizing differentiation. Based on these data, isoform-specific targeting RAR? may be more effective than pan-RAR inhibitors for regenerative therapies that seek to expand the K5+ progenitor cell pool.RAR? and RAR? reciprocally control K5+ progenitor cell proliferation and distribution in the developing submandibular salivary epithelium in a cell cycle-dependent manner while regulating lumenization independently of keratinizing differentiation.

Dataset Information

Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

Publications

Spatiotemporal expansion of primary progenitor zones in the developing human cerebellum.

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