E and ID proteins regulate cell chirality and left–right asymmetric development in Drosophila

Abstract

How left–right (LR) asymmetric forms in the animal body is a fundamental problem in Developmental Biology. Although the mechanisms for LR asymmetry are well studied in some species, they are still poorly understood in invertebrates. We previously showed that the intrinsic LR asymmetry of cells (designated as cell chirality) drives LR asymmetric development in the Drosophila embryonic hindgut, although the machinery of the cell chirality formation remains elusive. Here, we found that the Drosophila homologue of the Id gene, extra macrochaetae (emc), is required for the normal LR asymmetric morphogenesis of this organ. Id proteins, including Emc, are known to interact with and inhibit E‐box‐binding proteins (E proteins), such as Drosophila Daughterless (Da). We found that the suppression of da by wild‐type emc was essential for cell chirality formation and for normal LR asymmetric development of the embryonic hindgut. Myosin ID (MyoID), which encodes the Drosophila Myosin ID protein, is known to regulate cell chirality. We further showed that Emc‐Da regulates cell chirality formation, in which Emc functions upstream of or parallel to MyoID. Abnormal Id‐E protein regulation is involved in various human diseases. Our results suggest that defects in cell shape may contribute to the pathogenesis of such diseases.

Physiology, Development, and Disease Modeling in the Drosophila Excretory System

“…Given the colocalization of MyoID with the actin cytoskeleton in the hindgut, and the similarity of MyoID mutant phenotypes with dominant negative mutants in the actin-regulating Rho family GTPases Rho, Rac, and Cdc42, it is likely that the actin cytoskeleton plays a critical role in L/R hindgut asymmetry (Hozumi et al 2006;Spéder et al 2006). Additional cell chirality factors continue to be identified, including the transcriptional regulator Extra MacroChaetae and its binding partner Daughterless (Ishibashi et al 2019). It will be interesting to determine whether unique segments of the hindgut drive looping.…”

Statistical Validation Verifies That Enantiomorphic States of Chiral Cells Are Determinant Dictating the Left- or Right-Handed Direction of the Hindgut Rotation in Drosophila

“…The active force that drives hindgut rotation is generated by the hindgut epithelial tube [25,26]. Before rotation, the apical boundaries of the hindgut epithelial cells slant to the left relative to the organ's anterior-posterior axis [25,[27][28][29]. Given the apical-basal polarity of the hindgut epithelial cells, their three-dimensional structure is chiral [27].…”

“…Drosophila has been used as a model system to study the genetic mechanisms underlying the formation of cell chirality [27,29,32]. MyosinID (MyoID), a Myosin I family gene that is also called Myosin31DF, can induce dextral cell chirality, so that MyoID loss-of-function mutations result in sinistral cell chirality and the LR-inversion of various organs, including the embryonic hindgut, that have dextral LR-asymmetry in wild-type animals [20,25,[27][28][29][30]32,40]. MyosinIC (MyoIC), a Myosin I family gene that is also called Myosin61F, can induce sinistral cell chirality, which leads to the LR-inversion of several organs with handedness when overexpressed [17,26,40,41].…”

“…MyosinIC (MyoIC), a Myosin I family gene that is also called Myosin61F, can induce sinistral cell chirality, which leads to the LR-inversion of several organs with handedness when overexpressed [17,26,40,41]. We previously found that loss-of-function mutations of the extra macrochaetae (emc) gene, the Drosophila ortholog of Id, randomizes hindgut handedness [29]. Id family genes encode class V helix-loop-helix (HLH) proteins that inhibit E-box proteins-a class of basic HLH transcriptional factors, such as Daughterless (Da) in Drosophila-by forming a heterodimer, thereby regulating the balance between cell differentiation and cell proliferation [42].…”

“…Id family genes encode class V helix-loop-helix (HLH) proteins that inhibit E-box proteins-a class of basic HLH transcriptional factors, such as Daughterless (Da) in Drosophila-by forming a heterodimer, thereby regulating the balance between cell differentiation and cell proliferation [42]. We found that MyoID functions downstream of or parallel to emc in the formation of cell chirality [29]. Although the genetic mechanisms that create cell chirality are becoming clearer, a causal relationship between cell chirality and hindgut rotation is supported only by an apparent concordance between the enantiomorphic (sinistral or dextral) state of chiral cells and the direction of hindgut rotation in various mutants, along with the results of computer simulations recapitulating the rotation of the model gut tube driven by the dissolution of cell chirality [25,27].…”