Microtubule-associated protein 1 A and tubby act independently in regulating the localization of stereocilin to the tips of inner ear hair cell stereocilia.

Tubby mice exhibit hearing impairment due to the loss of stereocilin from the tip regions that connect the tallest stereocilia of the outer hair cells (OHCs) to the tectorial membrane. Stereocilin is an essential stereociliary protein in the OHCs, the mutation of which in humans causes autosomal recessive non-syndromic deafness. Map1a is a modifier of tubby hearing (moth1), and its wild-type allele, rather than the moth1 allele from the C57BL/6 J strain, restores stereocilin localization to the stereocilia and rescues the hearing impairment of tubby mice. The mechanism by which MAP1A accomplishes this is unclear, partly due to ambiguity regarding whether the tubby mutation is a true null. We therefore generated Tub-null (Tub-/-) mice by deleting exon 3 and found that they exhibit hearing impairment like that of tubby mice, suggesting the tubby mutation is a loss-of-function mutation with regard to hearing. When we crossed Tub-/- mice with AKR mice that have wild-type Map1a alleles, we found that wild-type MAP1A restores stereocilin localization to the tips of stereocilia and rescues hearing impairment. These data suggest MAP1A does not require interaction with tubby protein in maintaining stereocilin at the tips of stereocilia and that OHCs use two independent molecules-MAP1A and tubby-to doubly ensure proper stereocilin localization.

Neural regulation of energy and bone homeostasis by the synaptic adhesion molecule Calsyntenin-3.

Neuronal regulation of energy and bone metabolism is important for body homeostasis. Many studies have emphasized the importance of synaptic adhesion molecules in the formation of synapses, but their roles in physiology still await further characterization. Here, we found that the synaptic adhesion molecule Calsyntenin-3 (CLSTN3) regulates energy and bone homeostasis. Clstn3 global knockout mice show reduced body mass with improved leptin sensitivity and increased energy expenditure compared to their wild-type littermates. In addition, Clstn3 knockout mice show reduced marrow volume and cortical bone mass without alteration of trabecular bone microarchitecture. This reduced bone mass is not bone cell-autonomous because neither osteoblast- nor osteoclast-specific Clstn3 knockout mice show bone defects; similarly, in vitro cultures of both Clstn3 knockout osteoblasts and osteoclasts do not show any defects. These reduced body and bone mass phenotypes can be attributed instead to neuronal CLSTN3 because they are recapitulated by pan-neuronal but not sympathetic neuron-specific deletion of Clstn3. This study reveals novel physiological functions of neuronal Clstn3 as a key regulator of energy and bone homeostasis.