Hobert O et al. (1998) Biol Bull "A common theme for LIM homeobox gene function across phylogeny?"

Ruvkun GB, Hobert O

[Biol Bull, 1998]

The identification of the molecular components of the developmental neurogenic programs in different organisms has revealed an astounding degree of conservation across phylogeny, suggesting that the basic mechanisms of neural development have also been conserved in evolution. One class of conserved neural regulatory genes, the LIM homeobox genes, encode transcription factors with two Zn-finger-like LIM domains and a DNA-binding homeodomain. Vertebrate members of this class have been implicated in neurogenesis by correlative expression evidence: e.g., the combinatorial expression of LIM homeobox genes in the vertebrate spinal cord suggested a "LIM-code" for specific motorneuronal targeting choices. Genetic analysis in Drosophila also demonstrated their essential role in axon pathfinding and the determination of neurotransmitter identity. The genome of the nematode Caenorhabditis elegans is almost completely sequenced, thus allowing the analysis of complete gene families in a metazoan organism. C. elegans contains seven LIM homeobox genes. Almost all C. elegans LIM homeobox genes fall into subclasses that are defined by the presence of similar genes from arthropods and vertebrates, suggesting a common origin for different subclasses of LIM homeobox genes.

Hobert O et al. (2000) Trends Genet "Functions of LIM-homeobox genes."

Westphal H, Hobert O

[Trends Genet, 2000]

Homeobox genes play fundamental roles in development. They can be subdivided into several subfamilies, one of which is the LIM-homeobox subfamily. The primary structure of LIM-homeobox genes has been remarkably conserved through evolution. Have their functions similarly been conserved? A host of new data has been derived from mutational analysis in diverse organisms, such as nematodes, flies and vertebrates. These studies have revealed a prominent involvement of LIM-homeodomain proteins in tissue patterning and differentiation, and their function in neural patterning is evident in all organisms studied to date. Here, we summarize the recent findings on LIM-homeobox gene function, compare the function of these genes from different organisms and describe specific co-factor requirements.

Labouesse M et al. (2003) Curr Biol "Cell adhesion: parallels between vertebrate and invertebrate focal adhesions."

Georges-Labouesse E, Labouesse M

[Curr Biol, 2003]

Recent studies highlight the striking similarity between vertebrate focal adhesion plaques and Caenorhabditis elegans muscle adhesion structures and position LIM domain proteins as central players at focal adhesions.

Opperman CH et al. (1992) Parasitol Today "Nematode acetylcholinesterases--molecular forms and their potential role in nematode behavior."

Chang S-H, Opperman CH

[Parasitol Today, 1992]

Nematode movement is reliant upon the somatic musculature that runs longitudinally along the body wall. Neuromuscular synapses occur in the ventral and dorsal cords and employ the excitatory neurotransmitter, acetylcholine (ACh), for modulation of muscle activity. Acetylcholine activity is terminated by hydrolysis by acetylcholinesterase (AChE). Here, Charles Opperman and Stella Chang discuss the molecular forms and potential role of this enzyme.

Kemphues KJ et al. (1997) Trends in Cell Biology "Antisense RNA injection in Caenorhabditis elegans."

Mello CC, Kemphues KJ

[Trends in Cell Biology, 1997]

Antisense knockout techniques are also being used in worm embryos to inactivate transcripts and look at the effects. This method was pioneered by Su Guo and Ken Kemphues in 1995, initially to verify that the clone they had isolated corresponded to the par-1 gene, and now has been used by a large number of groups studying a variety of different genes.

Johnson JE et al. (2011) Curr Top Dev Biol "Notch-independent functions of CSL."

Macdonald RJ, Johnson JE

[Curr Top Dev Biol, 2011]

Notch-dependent CSL transcription complexes control essential biological processes such as cell proliferation, differentiation, and cell-fate decisions in diverse developmental systems. The orthologous proteins CBF1/Rbpj (mammalian), Su(H) (Drosophila), and Lag-1 (Caenorhabditis elegans) compose the CSL family of sequence-specific DNA-binding transcription factors. The CSL proteins are best known for their role in canonical Notch signaling. However, CSL factors also form transcription complexes that can function independent of Notch signaling and include repression and activation of target gene transcription. Because the different complexes share CSL as a DNA-binding subunit, they can control overlapping sets of genes; but they can also control distinct sets when partnered with tissue-specific cofactors that restrict DNA-sequence recognition or stability of the DNA-bound complex. The Notch-independent functions of CSL and the processes they regulate will be reviewed here with a particular emphasis on the tissue-specific CSL-activator complex with the bHLH factor Ptf1a.

Kratsios P et al. (2024) Development "Almost 40 years of studying homeobox genes in C. elegans."

Hobert O, Kratsios P

[Development, 2024]

Homeobox genes are among the most deeply conserved families of transcription factor-encoding genes. Following their discovery in Drosophila, homeobox genes arrived on the Caenorhabditis elegans stage with a vengeance. Between 1988 and 1990, just a few years after their initial discovery in flies and vertebrates, positional cloning and sequence-based searches showed that C. elegans contains HOX cluster genes, an apparent surprise given the simplicity and non-segmented body plan of the nematode, as well as many other non-clustered homeobox genes of all major subfamilies (e.g. LIM, POU, etc.). Not quite 40 years later, we have an exceptionally deep understanding of homeodomain protein expression and function in C. elegans, revealing their prevalent role in nervous system development. In this Spotlight, we provide a historical perspective and a non-comprehensive journey through the C. elegans homeobox field and discuss open questions and future directions.

Liu G et al. (2019) Biochim Biophys Acta Gene Regul Mech "Enhancer long-range contacts: The multi-adaptor protein LDB1 is the tie that binds."

Dean A, Liu G

[Biochim Biophys Acta Gene Regul Mech, 2019]

The eukaryotic genome is organized at varying levels into chromosome territories, transcriptional compartments and topologically associating domains (TADs), which are architectural features largely shared between different cell types and across species. In contrast, within TADs, chromatin loops connect enhancers and their target genes to establish unique transcriptomes that distinguish cells and tissues from each other and underlie development and differentiation. How these tissue-specific and temporal stage-specific long-range contacts are formed and maintained is a fundamental question in biology. The widely expressed Lim domain binding 1 protein, LDB1, plays a critical role in connecting enhancers and genes by forming complexes with cell-type specificity across diverse developmental pathways including neurogenesis, cardiogenesis, retinogenesis and hematopoiesis. Here we review the multiple roles of LDB1 in cell fate determination and in chromatin loop formation, with an emphasis on mammalian systems, to illuminate how LDB1 functions in normal cells and in diseases such as cancer.

Killeen MT et al. (2008) Dev Biol "Netrin, Slit and Wnt receptors allow axons to choose the axis of migration."

Killeen MT, Sybingco SS

[Dev Biol, 2008]

One of the challenges to understanding nervous system development has been to establish how a fairly limited number of axon guidance cues can set up the patterning of very complex nervous systems. Studies on organisms with relatively simple nervous systems such as Drosophila melanogaster and C. elegans have provided many insights into axon guidance mechanisms. The axons of many neurons migrate along both the dorsal-ventral axis (DV) and the anterior-posterior (AP) at different phases of development, and in addition they may also cross the midline. Axon migration in the dorsal-ventral (DV) direction is mainly controlled by Netrins with their receptors; UNC-40/DCC and UNC-5, and the Slits with their receptors; Robo/SAX-3. Axon guidance in the anterior-posterior (AP) axis is mainly controlled by Wnts with their receptors; the Frizzleds/Fz. An individual axon may be subjected to opposing attractive and repulsive forces coming from opposite sides in the same axis but there may also be opposing cues in the other axis of migration. All the information from the cues has to be integrated within the growth cone at the leading edge of the migrating axon to elicit a response. Recent studies have provided insight into how this is achieved. Evidence suggests that the axis of axon migration is determined by the manner in which Netrin, Slit and Wnt receptors are polarized (localized) within the neuron prior to axon outgrowth. The same molecules are involved in both axon outgrowth and axon guidance, for at least some neurons in C. elegans, whether the cue is the attractive cue UNC-6/Netrin working though UNC-40/DCC or the repulsive cue SLT-1/Slit working though the receptor SAX-3/Robo (Adler et al., 2006, Chang et al., 2006, Quinn et al., 2006, 2008). The molecules involved in cell signaling in this case are polarized within the cell body of the neuron before process outgrowth and direct the axon outgrowth. Expression of the Netrin receptor UNC-40/DCC or the Slit receptor SAX-3/Robo in axons that normally migrate in the AP direction causes neuronal polarity reversal in a Netrin and Slit independent manner (Levy-Strumpf and Culotti 2007, Watari-Goshima et al., 2007). Localization of the receptors in this case is caused by the kinesin-related VAB-8L which appears to govern the site of axon outgrowth in these neurons by causing receptor localization. Therefore, asymmetric localization of axon guidance receptors is followed by axon outgrowth in vivo using the receptor''s normal cue, either attractive, repulsive or unknown cues.

Burglin TR et al. (2016) Chromosoma "Homeodomain proteins: an update."

Burglin TR, Affolter M

[Chromosoma, 2016]

Here, we provide an update of our review on homeobox genes that we wrote together with Walter Gehring in 1994. Since then, comprehensive surveys of homeobox genes have become possible due to genome sequencing projects. Using the 103 Drosophila homeobox genes as example, we present an updated classification. In animals, there are 16 major classes, ANTP, PRD, PRD-LIKE, POU, HNF, CUT (with four subclasses: ONECUT, CUX, SATB, and CMP), LIM, ZF, CERS, PROS, SIX/SO, plus the TALE superclass with the classes IRO, MKX, TGIF, PBC, and MEIS. In plants, there are 11 major classes, i.e., HD-ZIP (with four subclasses: I to IV), WOX, NDX, PHD, PLINC, LD, DDT, SAWADEE, PINTOX, and the two TALE classes KNOX and BEL. Most of these classes encode additional domains apart from the homeodomain. Numerous insights have been obtained in the last two decades into how homeodomain proteins bind to DNA and increase their specificity by interacting with other proteins to regulate cell- and tissue-specific gene expression. Not only protein-DNA base pair contacts are important for proper target selection; recent experiments also reveal that the shape of the DNA plays a role in specificity. Using selected examples, we highlight different mechanisms of homeodomain protein-DNA interaction. The PRD class of homeobox genes was of special interest to Walter Gehring in the last two decades. The PRD class comprises six families in Bilateria, and tinkers with four different motifs, i.e., the PAIRED domain, the Groucho-interacting motif EH1 (aka Octapeptide or TN), the homeodomain, and the OAR motif. Homologs of the co-repressor protein Groucho are also present in plants (TOPLESS), where they have been shown to interact with small amphipathic motives (EAR), and in yeast (TUP1), where we find an EH1-like motif in MAT2.