Author Correction: Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1.

In Figs. 1e and 2g of this Letter, the labels 'actin' and 'VGLUT3', respectively, should have been in red instead of green font. This has been corrected online.

Trans-differentiation of outer hair cells into inner hair cells in the absence of INSM1.

The mammalian cochlea contains two types of mechanosensory hair cell that have different and critical functions in hearing. Inner hair cells (IHCs), which have an elaborate presynaptic apparatus, signal to cochlear neurons and communicate sound information to the brain. Outer hair cells (OHCs) mechanically amplify sound-induced vibrations, providing enhanced sensitivity to sound and sharp tuning. Cochlear hair cells are solely generated during development, and hair cell death-most often of OHCs-is the most common cause of deafness. OHCs and IHCs, together with supporting cells, originate in embryos from the prosensory region of the otocyst, but how hair cells differentiate into two different types is unknown1-3. Here we show that Insm1, which encodes a zinc finger protein that is transiently expressed in nascent OHCs, consolidates their fate by preventing trans-differentiation into IHCs. In the absence of INSM1, many hair cells that are born as OHCs switch fates to become mature IHCs. To identify the genetic mechanisms by which Insm1 operates, we compared the transcriptomes of immature IHCs and OHCs, and of OHCs with and without INSM1. In OHCs that lack INSM1, a set of genes is upregulated, most of which are normally preferentially expressed by IHCs. The homeotic cell transformation of OHCs without INSM1 into IHCs reveals a mechanism by which these neighbouring mechanosensory cells begin to differ: INSM1 represses a core set of early IHC-enriched genes in embryonic OHCs and makes them unresponsive to an IHC-inducing gradient, so that they proceed to mature as OHCs. Without INSM1, some of the OHCs in which these few IHC-enriched transcripts are upregulated trans-differentiate into IHCs, identifying candidate genes for IHC-specific differentiation.

Insm1 promotes neurogenic proliferation in delaminated otic progenitors.

INSM1 is a zinc-finger protein expressed throughout the developing nervous system in late neuronal progenitors and nascent neurons. In the embryonic cortex and olfactory epithelium, Insm1 may promote the transition of progenitors from apical, proliferative, and uncommitted to basal, terminally-dividing and neuron producing. In the otocyst, delaminating and delaminated progenitors express Insm1, whereas apically-dividing progenitors do not. This expression pattern is analogous to that in embryonic olfactory epithelium and cortex (basal/subventricular progenitors). Lineage analysis confirms that auditory and vestibular neurons originate from Insm1-expressing cells. In the absence of Insm1, otic ganglia are smaller, with 40% fewer neurons. Accounting for the decrease in neurons, delaminated progenitors undergo fewer mitoses, but there is no change in apoptosis. We conclude that in the embryonic inner ear, Insm1 promotes proliferation of delaminated neuronal progenitors and hence the production of neurons, a similar function to that in other embryonic neural epithelia. Unexpectedly, we also found that differentiating, but not mature, outer hair cells express Insm1, whereas inner hair cells do not. Insm1 is the earliest known gene expressed in outer versus inner hair cells, demonstrating that nascent outer hair cells initiate a unique differentiation program in the embryo, much earlier than previously believed.

Dehydration-anorexia derives from a reduction in meal size, but not meal number.

The anorexia that results from extended periods of cellular dehydration is an important physiological adaptation that limits the intake of osmolytes from food and helps maintain the integrity of fluid compartments. The ability to experimentally control both the development and reversal of anorexia, together with the understanding of underlying hormonal and neuropeptidergic signals, makes dehydration (DE)-anorexia a powerful model for exploring the interactions of neural networks that stimulate and inhibit food intake. However, it is not known which meal parameters are affected by cellular dehydration to generate anorexia. Here we use continuous and high temporal resolution recording of food and fluid intake, together with a drinking-explicit method of meal pattern analysis to explore which meal parameters are modified during DE-anorexia. We find that the most important factor responsible for DE-anorexia is the failure to maintain feeding behavior once a meal has started, rather than the ability to initiate a meal, which remains virtually intact. This outcome is consistent with increased sensitivity to satiation signals and post-prandial satiety mechanisms. We also find that DE-anorexia significantly disrupts the temporal distribution of meals across the day so that the number of nocturnal meals gradually decreases while diurnal meal number increases. Surprisingly, once DE-anorexia is reversed this temporal redistribution is maintained for at least 4 days after normal food intake has resumed, which may allow increased daily food intake even after normal satiety mechanisms are reinstated. Therefore, DE-anorexia apparently develops from a selective targeting of those neural networks that control meal termination, whereas meal initiation mechanisms remain viable.