ABSTRACT
Neurons are extraordinarily large and highly polarized cells that require rapid and efficient communication between cell bodies and axons over long distances. In peripheral neurons, transcripts are transported along axons to growth cones, where they are rapidly translated in response to extrinsic signals. While studying Tp53inp2, a transcript highly expressed and enriched in sympathetic neuron axons, we unexpectedly discovered that Tp53inp2 is not translated. Instead, the transcript supports axon growth in a coding-independent manner. Increasing evidence indicates that mRNAs may function independently of their coding capacity; for example, acting as a scaffold for functionally related proteins. The Tp53inp2 transcript interacts with the nerve growth factor (NGF) receptor TrkA, regulating TrkA endocytosis and signaling. Deletion of Tp53inp2 inhibits axon growth in vivo, and the defects are rescued by a non-translatable form of the transcript. Tp53inp2 is an atypical mRNA that regulates axon growth by enhancing NGF-TrkA signaling in a translation-independent manner.
Subject(s)
Nerve Growth Factor/metabolism , Neuronal Outgrowth/genetics , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , RNA, Messenger/metabolism , Receptor, trkA/metabolism , Transcription Factors/metabolism , Animals , Axons/metabolism , Endocytosis , Growth Cones/metabolism , HEK293 Cells , HeLa Cells , Humans , Mice , Neurons , PC12 Cells , RNA, Untranslated/metabolism , Rats , Rats, Sprague-Dawley , Signal Transduction , Superior Cervical Ganglion/cytologyABSTRACT
Down syndrome is the most common chromosomal disorder affecting the nervous system in humans. To date, investigations of neural anomalies in Down syndrome have focused on the central nervous system, although dysfunction of the peripheral nervous system is a common manifestation. The molecular and cellular bases underlying peripheral abnormalities have remained undefined. Here, we report the developmental loss of sympathetic innervation in human Down syndrome organs and in a mouse model. We show that excess regulator of calcineurin 1 (RCAN1), an endogenous inhibitor of the calcineurin phosphatase that is triplicated in Down syndrome, impairs neurotrophic support of sympathetic neurons by inhibiting endocytosis of the nerve growth factor (NGF) receptor, TrkA. Genetically correcting RCAN1 levels in Down syndrome mice markedly improves NGF-dependent receptor trafficking, neuronal survival and innervation. These results uncover a critical link between calcineurin signalling, impaired neurotrophin trafficking and neurodevelopmental deficits in the peripheral nervous system in Down syndrome.
Subject(s)
Down Syndrome/metabolism , Gene Expression Regulation/physiology , Intracellular Signaling Peptides and Proteins/metabolism , Muscle Proteins/metabolism , Nerve Growth Factors/metabolism , Protein Transport/physiology , Sympathetic Nervous System/growth & development , Animals , Calcium-Binding Proteins , Dynamin I/genetics , Dynamin I/metabolism , Endocytosis , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mice , Mice, Inbred Strains , Muscle Proteins/genetics , Nerve Growth Factors/genetics , Phosphorylation , Receptor, trkA/genetics , Receptor, trkA/metabolism , Sympathetic Nervous System/metabolism , Tyrosine 3-Monooxygenase/genetics , Tyrosine 3-Monooxygenase/metabolismABSTRACT
Feedback inhibition of adenylyl cyclase III (ACIII) via Ca(2+)-induced phosphorylation has long been hypothesized to contribute to response termination and adaptation of olfactory sensory neurons (OSNs). To directly determine the functional significance of this feedback mechanism for olfaction in vivo, we genetically mutated serine(1076) of ACIII, the only residue responsible for Ca(2+)-induced phosphorylation and inhibition of ACIII (Wei et al., 1996, 1998), to alanine in mice. Immunohistochemistry and Western blot analysis showed that the mutation affects neither the cilial localization nor the expression level of ACIII in OSNs. Electroolfactogram analysis showed no differences in the responses between wild-type and mutant mice to single-pulse odorant stimulations or in several stimulation paradigms for adaptation. These results suggest that phosphorylation of ACIII on serine(1076) plays a far less important role in olfactory response attenuation than previously thought.
