Biology subjects

Lozovska, A.

Publications and source records attributed to Lozovska, A..

4 recordsLinked to original sources

bioRxiv2025

Identification of non-coding elements associated with the evolutionary loss of digit 1.

Evolutionary loss of digits and limbs occurred many times during the diversification of tetrapods. The limbs of the earliest tetrapods were polydactylous, bearing as many 8 digits, but after the pentadactyly (five digits) was stabilized, no lineage evolved more than five digits per limb but many underwent digit loss. Within mammals, digit 1 (thumb on the forelimb or hallux on the hindlimb) is lost most frequently and is typically the first digit to disappear. Evidence from numerous studies of limb development shows that digit 1 development is controlled by mechanisms that are at least partially independent of the posterior 4 digits. In addition, evolutionary loss of digit 1 occurred independently in forelimbs and hindlimbs. Despite the frequency of digit loss in mammals, the underlying genetic mechanisms have not been uncovered. We used comparative genomics and bioinformatics to reconstruct the evolutionary history of genomic changes associated with digit 1 loss in the forelimbs and/or hindlimbs of 65 mammalian species. We identified a set of conserved non-coding elements that evolved in concert with independent (parallel) losses of digit 1. These elements, which are frequently near genes with known roles in digit development, underwent accelerated evolution in digit-reduced lineages. Furthermore, we find that elements with accelerated rates of evolution show significant loss of binding sites for transcription factors that are crucial for anterior digit development. The results suggest that cis-regulatory elements important for the development of digit 1 are evolutionarily accelerated in mammalian lineages that underwent reduction and loss of digit 1.

evolutionary biology↗

bioRxiv2023

Tgfbr1 regulates lateral plate mesoderm and endoderm reorganization during the trunk to tail transition

During the trunk to tail transition the mammalian embryo builds the outlets for the intestinal and urogenital tracts, lays down the primordia for the hindlimb and external genitalia, and switches from the epiblast/primitive streak to the tailbud as the driver of axial extension. Genetic and molecular data indicate that Tgfbr1 is a key regulator of the trunk to tail transition. Tgfbr1 has been shown to control the switch of the neuro mesodermal-competent cells from the epiblast to the chordo-neural hinge to generate the tail bud. We now show that Tgfbr1 signaling also controls the remodeling of the lateral plate mesoderm (LPM) and of the embryonic endoderm associated with the trunk to tail transition. In the absence of Tgfbr1 the two LPM layers do not converge at the end of the trunk, extending instead as separate layers enclosing the celomic cavity until the caudal embryonic extremity, and failing to activate markers of primordia for the hindlimb and external genitalia. However, this extended LPM, does not exhibit the molecular signatures characteristic of this tissue in the trunk. The vascular remodeling involving the dorsal aorta and the umbilical artery leading to the connection between embryonic and extraembryonic circulation was also affected in the Tgfbr1 mutant embryos. Similar alterations in the LPM and vascular system were also observed in Isl1 null mutants, indicating that this factor acts in the regulatory cascade downstream of Tgfbr1 in LPM-derived tissues. In addition, in the absence of Tgfbr1 the embryonic endoderm fails to expand to form the endodermal cloaca and to extend posteriorly to generate the tail gut. We present evidence suggesting that the remodeling activity of Tgfbr1 in the LPM and endoderm results from the control of the posterior primitive streak fate after its regression during the trunk to tail transition. Our data, together with previously reported observations, place Tgfbr1 at the top of the regulatory processes controlling the trunk to tail transition.

developmental biology↗

bioRxiv2023

Tgfbr1 controls developmental plasticity between the hindlimb and external genitalia by remodeling their regulatory landscape

The hindlimb and external genitalia of present-day tetrapods are thought to derive from an ancestral common primordium that evolved to generate a wide diversity of structures adapted for efficient locomotion and mating in the ecological niche conquered by the species. We show that despite long evolutionary distance from the ancestral condition, the early primordium of the mouse external genitalia preserved the capacity to take hindlimb fates. In the absence of Tgfbr1, the pericloacal mesoderm generates an extra pair of hindlimbs at the expense of the external genitalia. It has been shown that the hindlimb and the genital primordia share many of their key regulatory factors. Tgfbr1 controls the response to those factors by modulating the accessibility status of regulatory elements that control the gene regulatory networks leading to the formation of genital or hindlimb structures. Our work uncovers a remarkable tissue plasticity with potential implications in the evolution of the hindlimb/genital area of tetrapods, and identifies a novel mechanism for Tgfbr1 activity that might also contribute to the control of other physiological or pathological processes.

developmental biology↗

bioRxiv2020

A TgfβRI/Snai1-dependent developmental module at the core of vertebrate axial elongation

Formation of the vertebrate postcranial body axis follows two sequential but distinct phases. The first phase generates pre-sacral structures (the so-called primary body) through the activity of the primitive streak (PS) on axial progenitors within the epiblast. The embryo then switches to generate the secondary body (post-sacral structures), which depends on axial progenitors in the tail bud. Here we show that the mammalian tail bud is generated through an independent developmental module, concurrent but functionally different to that generating the primary body. This module is triggered by convergent Tgf{beta}RI and Snai1 activities that promote an incomplete epithelial to mesenchymal transition (EMT) on a subset of epiblast axial progenitors. This EMT is functionally different to that coordinated by the PS, as it does not lead to mesodermal differentiation but brings axial progenitors into a transitory state, keeping their progenitor activity to drive further axial body extension.

developmental biology↗