Journal
DEVELOPMENT
Volume 139, Issue 21, Pages 4062-4071Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.082321
Keywords
Arl13b; Cilia; Neural tube patterning; Sonic hedgehog; Mouse
Categories
Funding
- National Institutes of Health [R01NS056380]
- Burroughs Wellcome Fund (Hitchings Elion Career Development Award)
- American Heart Association predoctoral fellowship [11PRE7200011]
- National Institute of General Medical Sciences [T32GM008490]
- Microscopy Core of the Emory Neuroscience National Institute of Neurological Disorders and Stroke Core Facilities [P30NS055077]
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Cilia are necessary for sonic hedgehog (Shh) signaling, which is required to pattern the neural tube. We know that ventral neural cell fates are defined by a specific cohort of transcription factors that are induced by distinct thresholds of Shh activity mediated by opposing gradients of Gli activator (GliA) and Gli repressor (GliR). Despite this understanding, the role of Shh as an instructive morphogen is viewed as increasingly complex, with current models integrating positive inputs in terms of ligand concentration and time, along with negative feedback via the downstream gene regulatory network. To investigate the relative contributions of the positive and negative inputs from Shh signaling in neural patterning, we took advantage of a protein that uncouples the regulation of GliA and GliR: the cilia protein ADP-ribosylation factor-like 13b (Arl13b). By deleting Arl13b in mouse, we induced low-level constitutive GliA function at specific developmental stages and defined a crucial period prior to E10.5 when shifts in the level of GliA cause cells to change their fate. Strikingly, we found that improperly patterned cells in these mice converted to the wild-type pattern by E12.5. We further showed that the recovery of patterning did not occur when we also deleted Gli3, the primary GliR in the neural tube, revealing a crucial role of Gli3 in the maintenance of neural patterning.
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