Biology subjects

Ladher, R. K.

Publications and source records attributed to Ladher, R. K..

3 recordsLinked to original sources

bioRxiv2024

Mechanical coupling of compartments drives polarity and patterning of mouse auditory epithelium

Morphogenetic information arises from a combination of genetically encoded cellular properties and emergent cellular behaviours. The spatio-temporal implementation of this information is critical to ensure robust, reproducible tissue shapes, yet the principles underlying its organisation remain unknown. We investigated this principle using the mouse auditory epithelium, the organ of Corti (OC). OC consists of a sensory domain, which transduces sound through polar mechanosensory hair cells (HC), part of a mosaic with supporting cells (SC). On either side of the sensory domain are non-sensory domains. These domains undergo cellular rearrangements, which, together, lead to a spiral cochlea that contains planar polarised HCs. This makes the mammalian cochlea a compelling system to understand coordination across spatial scales. Using genetic and ex-vivo approaches, we found patterning of OC into sensory and non-sensory domains is associated with a combinatorial expression of adhesion molecules, which underpins OC into spatially defined compartments, enabling planar cell polarity (PCP) cues to regulate compartment-specific organisation. Through compartment-specific knockouts of the PCP protein, Vangl2, we find evidence of compartment coupling, a non-linear influence on the organisation within one compartment when cellular organisation is disrupted in another. In the OC, compartment coupling originates from vinculin-dependent junctional mechanics, coordinating cellular dynamics across spatial scales. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=115 SRC="FIGDIR/small/613243v2_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@11d31c1org.highwire.dtl.DTLVardef@1ad85dcorg.highwire.dtl.DTLVardef@12f4a0corg.highwire.dtl.DTLVardef@1a663ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

developmental biology↗

bioRxiv2024

Initiation and Formation of Stereocilia during the Development of Mouse Cochlear Hair Cells

Stereocilia are apically located actin-protrusions found on the hair cells of the inner ear. At least three rows of stereocilia are arranged in a graded staircase pattern, which is vital for mechanosensation. Stereocilia form soon after the specification of hair cells. While these steps have been well-characterized in the avian auditory epithelium, the equivalent information in mice is lacking. Using scanning electron microscopy and super-resolution microscopy, we investigate stereocilia formation from hair cell specification stages in the mouse organ of Corti. Even before differentiation, we find that sensory progenitors, which will give rise to both hair cells and support cells, have a dense lawn of microvilli. Hair cell specialisation is first apparent as an enrichment in junctional actin, followed by the relocalisation of kinocilium into an eccentric position and the thickening of hair cell microvilli closest to the kinocilium. To determine actin signatures associated with hair cell development, we use a new analytical method to map cellular actin filament distribution during development. By nomalising relative actin filament density, we obtain insights into cuticular plate development and actin redistribution during the earliest phases of hair cell specialisation.

developmental biology↗

bioRxiv2023

MORPHOGENIC VERSUS MITOGENIC ROLES OF SHH ARE SEGREGATED ON DISTINCT EXOSOMES REGULATED BY CELLULAR RAB7 LEVELS

The secreted signaling molecule, Sonic hedgehog (Shh) is involved in patterning and growth of various embryonic tissues across species. This lipid-anchored protein is secreted on extracellular vesicles to activate signaling. Shh has two functions during spinal cord development, acting as a morphogen to pattern the ventral neural tube and a mitogen to maintain neural progenitors. Here, we find that these activities are segregated on to two distinct pools of exosomes. Shh secreted on a classical exosomal pool (Shh-P150) is able to activate ventral threshold targets in the neural tube. In contrast, the mitogenic activity, is elicited by a lighter exosomal pool (Shh-P450). We further show that cellular environment plays a major role in regulating the biogenesis of P150 versus P450 by modulating Rab7 levels. We find that active Rab7 is necessary for ventral neural tube patterning through the regulation of Shh-P150 secretion. The cellular mechanisms involved in packaging and secretion of Shh with different partners on P150 or P450 pools may be more general, enabling the separation of functional activities of signaling molecules during development and disease.

developmental biology↗