Ciliary phosphatidylinositol phosphatase Inpp5e plays positive and negative regulatory roles in Shh signaling

Abstract

1 Inpp5e attenuates Sonic hedgehog signal transduction through a combination of positive and 2 negative regulatory roles that likely control the relative timing of Gli processing. 3 4 Abstract 5 6 Sonic hedgehog (Shh) signal transduction specifies ventral cell fates in the neural tube7 and is mediated by the Gli transcription factors that play both activator (GliA) and repressor 8 (GliR) roles. Cilia are essential for Shh signal transduction and the ciliary phosphatidylinositol 9 phosphatase, Inpp5e, is linked to Shh regulation. In the course of a forward genetic screen for 10 recessive mouse mutants, we identified a functional null allele of Inpp5e, ridge top (rdg), with 11 expanded ventral neural cell fates at E10.5. By E12.5, Inpp5e rdg/rdg embryos displayed normal 12 neural patterning and this correction over time required Gli3, the predominant repressor in 13 neural patterning. Inpp5e rdg function largely depended on the presence of cilia and on 14 Smoothened, the obligate transducer of Shh signaling, indicating Inpp5e functions within the 15 cilium to regulate the pathway. These data indicate that Inpp5e plays a more complicated role in 16 Shh signaling than previously appreciated. We propose that Inpp5e attenuates Shh signaling in 17

Signaling in the primary cilium through the lens of the Hedgehog pathway

“…Loss of TULP3 causes a failure of cilia proteins ARL13B and INPP5E to localize with the cilium (Han et al, ). Both ARL13B and INPP5E are known for their influence over vHH pathway components (Caspary et al, ; Chavez et al, ; Constable, Long, Floyd, Schurmans, & Caspary, ; Garcia‐Gonzalo et al, ; Larkins, Aviles, East, Kahn, & Caspary, ). Adenylyl cyclases (AC) are responsible for generating cyclic AMP (cAMP), the substrate required to activate protein kinase A (PKA), a negative HH regulator (Hammerschmidt et al, ).…”

“…In vitro, this results in a dampened vHH response (Chavez et al, ; Garcia‐Gonzalo et al, ). In vivo , Inpp5e mutants display increased SHH response in the caudal neural tube which corrects over time (Constable et al, ). It is unclear whether these differences are due to tissue‐specific context, the duration of signaling or another factor.…”

Defective INPP5E distribution in NPHP1‐related Senior–Loken syndrome

“…Interestingly, nephronophthisis and Joubert syndrome are two types of ciliopathies with overlapping clinical manifestations, including cystic kidney disease and retinal degeneration. Previous publications showed that NPHP1 and INPP5E mutations are responsible for Joubert syndrome (Constable et al, 2020; Jacoby et al, 2009). Our study shows that NPHP1 deletion results in the abnormal expression of INPP5E, which supports the hypothesis that Joubert syndrome and nephronophthisis represent the same biological disorder but with different versions of clinical manifestations.…”