MGRN1

Cilia effects upon perturbation of MGRN1

Ciliogenesis screen results (4 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-2.45) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381
• Pusapati et al. 2018 (CRISPR) [CRISPR]: Negative Regulator (Hh signaling, pos_rank=11, lfc=1.98) PMID:30270045

Phenotypes

Mouse phenotype:

abnormal ear morphology; increased freezing behavior; vacuolation; increased spleen weight; abnormal skin coloration; necrosis; preweaning lethality; incomplete penetrance; enlarged urinary bladder; increased circulating alkaline phosphatase level; increased neutrophil cell number; decreased bone mineral content; abnormal coat/hair pigmentation; enlarged lymph nodes; abnormal skin morphology; abnormal bone structure; decreased lymphocyte cell number; increased mean corpuscular hemoglobin; increased lymphocyte cell number

Mouse ciliopathy phenotype:

abnormal auditory brainstem response; abnormal uterus morphology; increased heart weight; shortened QRS complex duration; increased circulating bilirubin level; abnormal pancreas morphology; abnormal sternum morphology; abnormal cranium morphology

Subcellular localization

cilia associated gene, cytosol, endoplasmic reticulum, vesicles

Functional category

• Signaling (Hedgehog, GPCRs, ion channels)

Function

Starting from 147 Ub-related components with connections to cilia or Hedgehog signaling, we identified 40 genes whose loss altered Hedgehog signaling as measured by a Gli-GFP reporter. 9 of these 40 caused aberrant Smo accumulation in cilia at the basal state. The nine included an E2-conjugating enzyme (Ube2l3), four E3 ligases (Wwp1, Arih2, Mgrn1, and Maea), a deubiquitinating enzyme (DUB; Bap1), and three adaptors (Kctd5, Skp1a, and Skp2). The E3 ligases appear to function in discrete steps where Arih2 regulates cellular levels of Smo, Wwp1 regulates ciliary levels directly, and Mgrn1 and Maea function in the cytoplasm. Our findings shed light on the long-standing enigma of how the ciliary levels of Smo are regulated by Hedgehog signaling E3 ligase; LoF causes Smo accumulation in cilia at basal state (PMID: 34161574).