Extended Data Fig. 5 |. Schematic illustration of the various forms of transdifferentiation between IHCs and OHCs.

IHCs and OHCs are depicted from their onset after proliferation of progenitors has ceased (nascent, ~E14.5), through embryonic (E15.5 to E20.5) and postnatal (P0 to P9) stages, and into their adult form. As differentiation proceeds, hair cells acquire increasing numbers of characteristic markers (represented in red for IHCs and green for OHCs; nuclei are represented as blue disks). The course of normal development is indicated with black arrows. IHCs express TBX2 from their onset and throughout life. OHCs express INSM1 and BCL11b transiently during embryonic and early postnatal stages. Transitions due to genetic manipulations are indicated by colored arrows: red if leading to an IHC-like differentiation, and green if leading to an OHC-like differentiation. (1) Removal of INSM1 from nascent OHCs (−INSM1) results in about half of them expressing TBX2 and transdifferentiating into early IHCs (red arrow), which then proceed to differentiate into mature IHCs. The other half of INSM1 lacking OHCs do not express TBX2 and proceed to differentiate into mature OHCs (green). Note that, subsequent to its deletion, there is no expression of INSM1 (whose lable has been kept in the illustration for simplicity). (2) Removal of TBX2 from the onset of IHC formation (−TBX2) results in its switching to differentiate like an OHC, transiently expressing early markers INSM1 and BCL11b, and eventually maturing into OHCs like those of adults (albeit in the position of the IHCs, and hence termed ic-OHCs). (3) Removal of TBX2 from a postnatal (up to P9) IHC (−TBX2) results in its direct transdifferentiation into a differentiated OHC, without expressing early OHC markers INSM1 and BCL11b, and transiently co-expressing markers of both mature IHCs (VGLUT3) and OHCs (PMCA2 and Prestin), before proceeding to becoming OHC-like in most respects. (4) Ectopic expression of TBX2 in late embryonic OHCs (+TBX2) results in their transdifferentiation into IHCs (expressing VGLUT3 but not PMCA2 or Prestin). (5) In the absence of both INSM1 and TBX2, nascent IHCs (−INSM1 −TBX2) transdifferentiate into OHCs whereas nascent OHCs do not transdifferentiate into IHCs. In other words, Tbx2 is epistatic to Insm1.