Arvcf Dependent Adherens Junction Stability is Required to Prevent Age-Related Cortical Cataracts.

The etiology of age-related cortical cataracts is not well understood but is speculated to be related to alterations in cell adhesion and/or the changing mechanical stresses occurring in the lens with time. The role of cell adhesion in maintaining lens transparency with age is difficult to assess because of the developmental and physiological roles that well-characterized adhesion proteins have in the lens. This report demonstrates that Arvcf, a member of the p120-catenin subfamily of catenins that bind to the juxtamembrane domain of cadherins, is an essential fiber cell protein that preserves lens transparency with age in mice.

Formation and contraction of multicellular actomyosin cables facilitate lens placode invagination.

Embryonic morphogenesis relies on the intrinsic ability of cells, often through remodeling the cytoskeleton, to shape epithelial tissues during development. Epithelial invagination is an example of morphogenesis that depends on this remodeling but the cellular mechanisms driving arrangement of cytoskeletal elements needed for tissue deformation remain incompletely characterized. To elucidate these mechanisms, live fluorescent microscopy and immunohistochemistry on fixed specimens were performed on chick and mouse lens placodes.

Novel variants in CDH2 are associated with a new syndrome including Peters anomaly.

Peters anomaly (PA) is a congenital corneal opacity associated with corneo-lenticular attachments. PA can be isolated or part of a syndrome with most cases remaining genetically unsolved. Exome sequencing of a trio with syndromic PA and 145 additional unexplained probands with developmental ocular conditions identified a de novo splicing and three novel missense heterozygous CDH2 variants affecting the extracellular cadherin domains in four individuals with PA.

Folic acid modifies the shape of epithelial cells during morphogenesis via a Folr1 and MLCK dependent mechanism.

Folic acid supplementation can prevent neural tube defects, but the specific molecular mechanisms by which it does have not been elucidated. During neural plate morphogenesis, epithelial cell apical constriction cooperates with other events to drive tissue-bending, and when defective, can result in neural tube defects. A Rho-kinase deficient binding mutant of the apical constriction regulating protein, Shroom3 (Shroom3), is one of only a handful of mouse mutant lines with neural tube defects that can be rescued by folic acid supplementation.

The non-canonical Wnt-PCP pathway shapes the mouse caudal neural plate.

The last stage of neural tube (NT) formation involves closure of the caudal neural plate (NP), an embryonic structure formed by neuromesodermal progenitors and newly differentiated cells that becomes incorporated into the NT. Here, we show in mouse that, as cell specification progresses, neuromesodermal progenitors and their progeny undergo significant changes in shape prior to their incorporation into the NT. The caudo-rostral progression towards differentiation is coupled to a gradual reliance on a unique combination of complex mechanisms that drive tissue folding, involving pulses of apical actomyosin contraction and planar polarised cell rearrangements, all of which are regulated by the Wnt-PCP pathway.

deficiency leads to a syndrome of abnormal striatum, congenital cataract and intellectual disability.

Background: Voltage-gated potassium channels are highly diverse proteins representing the most complex class of voltage-gated ion channels from structural and functional perspectives. Deficiency of these channels usually results in various human disorders.

Objectives: To describe a novel autosomal recessive syndrome associated with deficiency leading to congenital cataract, abnormal striatum, intellectual disability and attention deficit hyperactivity disorder.

Lens placode planar cell polarity is dependent on Cdc42-mediated junctional contraction inhibition.

Development of the ocular lens commences with the formation of the lens placode, an epithelial structure that thickens and subsequently bends inward in a process called invagination. Invagination is observed during the development of many embryonic structures, but the spectrum of morphogenetic events driving this process are, in most cases, not fully understood. A characteristic commonly found in embryonic tissues undergoing epithelial reorganization is planar polarity, a property where cells are geometrically and/or molecularly orientated in a specific direction along the plane of an epithelium.

Thyroid bud morphogenesis requires CDC42- and SHROOM3-dependent apical constriction.

Early development of the gut endoderm and its subsequent remodeling for the formation of organ buds are accompanied by changes to epithelial cell shape and polarity. Members of the Rho-related family of small GTPases and their interacting proteins play multiple roles in regulating epithelial morphogenesis. In this study we examined the role of Cdc42 in foregut development and organ bud formation.

The interaction between Shroom3 and Rho-kinase is required for neural tube morphogenesis in mice.

Shroom3 is an actin-associated regulator of cell morphology that is required for neural tube closure, formation of the lens placode, and gut morphogenesis in mice and has been linked to chronic kidney disease and directional heart looping in humans. Numerous studies have shown that Shroom3 likely regulates these developmental processes by directly binding to Rho-kinase and facilitating the assembly of apically positioned contractile actomyosin networks. We have characterized the molecular basis for the neural tube defects caused by an ENU-induced mutation that results in an arginine-to-cysteine amino acid substitution at position 1838 of mouse Shroom3.

p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis.

Apical constriction (AC) is a widely utilized mechanism of cell shape change whereby epithelial cells transform from a cylindrical to conical shape, which can facilitate morphogenetic movements during embryonic development. Invertebrate epithelial cells undergoing AC depend on the contraction of apical cortex-spanning actomyosin filaments that generate force on the apical junctions and pull them toward the middle of the cell, effectively reducing the apical circumference. A current challenge is to determine whether these mechanisms are conserved in vertebrates and to identify the molecules responsible for linking apical junctions with the AC machinery.

Generation of an Rx-tTA: TetOp-Cre knock-in mouse line for doxycycline regulated Cre activity in the Rx expression domain.

Genetic deletion of mouse genes has played a crucial role in our understanding of embryonic eye development. Transgenic, tissue specific Cre recombinase expression in various eye structures has facilitated these experiments. However, an early expressing, temporally-regulated, optic vesicle-specific Cre line has not been available.

A Trio-RhoA-Shroom3 pathway is required for apical constriction and epithelial invagination.

Epithelial invagination is a common feature of embryogenesis. An example of invagination morphogenesis occurs during development of the early eye when the lens placode forms the lens pit. This morphogenesis is accompanied by a columnar-to-conical cell shape change (apical constriction or AC) and is known to be dependent on the cytoskeletal protein Shroom3.

Shroom3 and a Pitx2-N-cadherin pathway function cooperatively to generate asymmetric cell shape changes during gut morphogenesis.

The cytoskeletal protein Shroom3 is a potent inducer of epithelial cell shape change and is required for lens and neural plate morphogenesis. Analysis of gut morphogenesis in Shroom3 deficient mouse embryos revealed that the direction of gut rotation is also disrupted. It was recently established that Pitx2-dependent, asymmetrical cellular behaviors in the dorsal mesentery (DM) of the early mid-gut, a structure connecting the gut-tube to the rest of the embryo, contribute to the direction of gut rotation in chicken embryos by influencing the direction of the dorsal mesenteric tilt.

Pax6-dependent Shroom3 expression regulates apical constriction during lens placode invagination.

Embryonic development requires a complex series of relative cellular movements and shape changes that are generally referred to as morphogenesis. Although some of the mechanisms underlying morphogenesis have been identified, the process is still poorly understood. Here, we address mechanisms of epithelial morphogenesis using the vertebrate lens as a model system.

Microarray analysis of Tbx5-induced genes expressed in the developing heart.

Tbx5 is a member of the T-box family of transcription factors and is associated with Holt-Oram syndrome (HOS), a congenital disorder characterized by heart and limb defects. Although implicated in several processes during development, only a few genes regulated by Tbx5 have been reported. To identify candidate genes regulated by Tbx5 during heart development, a microarray approach was used.

T-box genes and heart development: putting the "T" in heart.

Members of the T-box gene family (Tbx) are essential for normal heart development, and mutations in human TBX genes cause congenital cardiovascular malformations. T-box genes have been implicated in early cardiac lineage determination, chamber specification, valvuloseptal development, and diversification of the specialized conduction system in vertebrate embryos. These genes include Tbx1, Tbx2, Tbx3, Tbx5, Tbx18, and Tbx20, all of which exhibit complex temporal spatial regulation in developing cardiac structures.

Differential expression and function of Tbx5 and Tbx20 in cardiac development.

The T-box transcription factors play critical roles in embryonic development including cell type specification, tissue patterning, and morphogenesis. Several T-box genes are expressed in the heart and are regulators of cardiac development. At the earliest stages of heart development, two of these genes, Tbx5 and Tbx20, are co-expressed in the heart-forming region but then become differentially expressed as heart morphogenesis progresses.