LEP

Cilia effects upon perturbation of LEP

Loss-of-function effect:

Shorter cilia

Overexpression effect:

Longer cilia

Ciliogenesis screen results (4 screens)

• Kim2016: No effect
• Wheway et al. 2015 (siRNA) [siRNA]: No effect PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: Hyper-ciliogenesis (robust z=3.24, ciliated=62.4%) PMID:26595381

Phenotypes

Mouse phenotype:

abnormal coat appearance, decreased total reti thickness, decreased grip strength, increased cornea thickness, decreased heart weight, decreased vertical activity, increased anxiety-related response, abnormal eye posterior chamber depth, abnormal reti inner nuclear layer morphology, decreased locomotor activity, decreased heart rate, decreased spleen weight, decreased exploration in new environment, increased cardiac stroke volume

Mouse ciliopathy phenotype:

short tibia, male infertility, prolonged qrs complex duration, female infertility

Human ciliopathy phenotype:

obesity due to congenital leptin deficiency

Subcellular localization

cilia associated gene

Functional category

• Ciliary assembly/disassembly
• Actin & cytoskeleton regulation
• Metabolism
• T cell biology
• Reproduction & sperm
• Protein processing & maturation
• Cell migration & adhesion
• Signaling (Hedgehog, GPCRs, ion channels)
• Cardiac & muscle development
• ECM & connective tissue
• Transcription regulation
• Cilia length regulation

Function

Treatment of N1 hypothalamic neuron cells with leptin stimulated cilia assembly via inhibition of the tumor suppressors PTEN and glycogen synthase ki se 3β (GSK3β). Induction of short cilia in the hypothalamus of adult mice increased food intake and decreased energy expenditure, leading to a positive energy balance. Mice with short hypothalamic cilia exhibited attenuated anorectic responses to leptin, insulin, and glucose, which indicates that leptin-induced cilia assembly is essential for sensing these satiety sig ls by hypothalamic neurons.( 24667636) . Leptin promotes cilium growth in hypothalamic neuronal cells by increasing intraflagellar transport gene transcription and F-actin rearrangement. (26041775) Neuronal cilia lengths were selectively reduced in hypothalami of obese mice with leptin deficiency and leptin resistance. Treatment of N1 hypothalamic neuron cells with leptin stimulated cilia assembly via inhibition of PTEN and GSK3β. (24667636)