Physical Mechanisms Bridging Gaps Between One Among Many Cellular Level Mechanisms Of A Gene Expression
In this thesis I have addressed physical mechanisms bridging gaps between one among many cellular level mechanisms (ref) of a gene expression that manifests to give rise to beneficial properties at tissue and organism level. I have demonstrated that this exclusive inversion of chromatin in photoreceptor rods is necessary and sufficient to explain the observed large angle scattering properties of the rod cell nuclei. Interestingly this relationship between chromatin state and light scattering properties of cells have been studied before for non-retinal cells (Drezek et al., 2003; Kirmes et al., 2015) to monitor the progression of cells from a healthy to a diseased state.
This study presents a comprehensive example of a biophysical basis and mechanism of biological transparency theoretically described by (Johnson 1997,2012) in a model organism that results in viable transparent tissues. The nocturnal vertebrate retina has adopted a similar mechanism where the sizes of sub tissue and cellular structures are tuned to render the cornea transparent while the sclera made of same collagen fibres is completely opaque (ref).
The strategy is also exhibited by deep marine animals for camouflage (Johnson 2001) (chromophores in octopus). The computational simulations of the light propagation give us access to the parameters that mechanistically describe emergent tissue optical effects stemming from the cell and subcellular optical phenotype giving rise to image transfer improvement in the mouse retina.Nocturnal nuclear adaptation - costs and benefitsThe unique chromatin distribution in the rod cells is a deviation from an evolutionary highly conserved pattern (Solovei 2016). It has sparked the interest of the scientists to study the unique epigenetic landscape to understand the regulatory principles of genome organisation. This mechanism has recently been described as a self-organised restructuring of the denser heterochromatin, phase separating into a central compact globular aggregate in the absence of its interactions with the nuclear lamina (Falk et al 2018).
Also, robust differentiation signals acting on the neuronal precursors ensure the unique genetic make-up of the rods (Hiler 2015). The deviation from a conventional arrangement, however seems to come with its costs. The DNA repair machinery is shown to be impaired in the rods (Frohns 2014). The rods are ss pliant and highly susceptible to apoptosis under stress (Dyer, 2016). Their reprogrammability is the lowest among the retinal cells (Wang 2018).In light of the findings presented in the thesis, it can be argued that these costs are compensated by the gain in optical properties of the tissue ultimately resulting in an increase in visual sensitivity for mice and other nocturnal mammals. It is worth mentioning that, in addition to chromatin distribution, the overall fraction of heterochromatin to euchromatin is shown to be different for the photoreceptors, constituting a 50:50 proportion as against a typical 90% dominance of euchromatin in other cell types (Wang 2018).
The greater mass of the heterochromatin allows for a larger aggregate to form resulting in a more closed and compact packing resulting in an overall reduced volume specific scattering (cref). When comparing the MTF of the WT and TG-LBR ONL, representation of the ratio of the transfer functions yields a curve very similar to a sharpening filter (cref). Fitting a model to such a function (ref) yields parameters that describe the operating range of the filter close to the visual acuity of mouse. Given the improved optics of the inverted architecture, it poses a question as to why the architecture is exclusive to nocturnal mammals (ref).Visibility and detectability of an object by a detector array is a function of image contrast, signal to noise, size of detector, amount of light and the quantum efficiency of the detector described by the following relation (Rose 1948). Resolution= C/k √(n/A) η (1)C=contrast, n=number of photons, A=total area of detector, k=signal to noise threshold k∈[3,5], η=quantum efficiency.For typical values of area of mouse retina and reported signal to noise and quantum efficiency values for rod photoreception (ref) we can construct a plot as shown in figurexx.
It can be seen that the resolution dictated by the above relationship is around 20cycles/deg for an illumination of about 100Lux (photopic vision). This value is well beyond the visual acuity range of mouse. Thus, any changes in image contrast (compare WT vs TG-LBR retina) will not have an effect in the physiological response of the mouse. The critical illumination is of the order of 100 mLux (scotopic vision) for mouse, below which changes in the contrast transmission vary within the visual acuity range.
This transition is experimentally observed in the behaviour of the animals where, there was no significant differences between the two mouse types for photopic illumination while the differences begin to show only at scotopic conditions. Similarly, for diurnal mammals such as human the critical illumination is about 25Lux which is well below the typical dwelling area illumination during the day. Moreover, there are additional morphological features such as the fovea that is responsible for high acuity vision in higher mammals where, the inner retinal layers are pushed aside to giving light access to the photoreceptor cells. We thus can appreciate the need for the nuclear adaptation exclusively to cater to the high sensitivity nocturnal vision.
