Hox gene functions in the C. elegans nervous system: From early patterning to maintenance of neuronal identity

Abstract

The nervous system emerges from a series of genetic programs that generate a remarkable array of neuronal cell types. Each cell type must acquire a distinct anatomical position, morphology, and function, enabling the generation of specialized circuits that drive animal behavior. How are these diverse cell types and circuits patterned along the anterior-posterior (A-P) axis of the animal body? Hox genes encode transcription factors that regulate cell fate and patterning events along the A-P axis of the nervous system. While most of our understanding of Hox-mediated control of neuronal development stems from studies in segmented animals like flies, mice, and zebrafish, important new themes are emerging from work in a non-segmented animal: the nematode Caenorhabditis elegans. Studies in C. elegans support the idea that Hox genes are needed continuously and across different life stages in the nervous system; they are not only required in dividing progenitor cells, but also in post-mitotic neurons during development and adult life. In C. elegans embryos and young larvae, Hox genes control progenitor cell specification, cell survival, and neuronal migration, consistent with their neural patterning roles in other animals. In late larvae and adults, C. elegans Hox genes control neuron type-specific identity features critical for neuronal function, thereby extending the Hox functional repertoire beyond early patterning. Here, we provide a comprehensive review of Hox studies in the C. elegans nervous system. To relate to readers outside the C. elegans community, we highlight conserved roles of Hox genes in patterning the nervous system of invertebrate and vertebrate animals. We end by calling attention to new functions in adult post-mitotic neurons for these paradigmatic regulators of cell fate.

Keywords: C. elegans; Cell migration; Cell survival; Hox transcription factors; Neural progenitors; Neuronal terminal identity.

Figure 1.. Spatial collinearity is conserved in the C. elegans Hox cluster.

(A) Depiction of Hox clusters in C. elegans (top) and Drosophila (bottom). Colors are used to depict the closely related orthologs. (B) Expression of Hox genes in C. elegans 1.5-fold embryo. (C) Expression of Hox genes in larval and adult stage C. elegans. A, Anterior; P, posterior; D, dorsal; V, ventral.

Figure 2.. Hox genes pattern the neuroectoderm in C. elegans.

(A) Expression of Hox genes in the P cell lineage at the L1 stage. (B) Lineage diagrams indicating the descendants from each P-derived neuroblast along the A-P axis of hermaphrodites (left) and males (right). Posterior P lineage (Pn.p) generates cells of the epidermis and is excluded. Red X indicates programmed cell death. Blue text indicates neurons discussed in C-F. (C) LIN-39 patterns sex-specific VC neurons in the hermaphrodite midbody P lineage. (D) LIN-39 patterns sex-specific CA/CP neurons in the male anterior and midbody P lineage. (E) MAB-5 patterns the VB motor neurons in both sexes and the posterior P12.aap lineage in males (F).

Figure 3.. Posterior Hox genes are selectors of sensory rays in the male tail.

(A) Schematic of the V cells and T cell which generate the sensory rays in the copulatory male tail. (B) (top) Lineage diagrams of V5, which generates the R1A-R1B ray neurons, V6, which generates the R2A-R6A and R2B-R2A ray neurons; (bottom) Summary of hox expression across post-mitotic ray neurons in the adult. (C) Adult C. elegans male with V6-derived rays (ray 2-6) indicated in black. (D)The anatomy of a ray, including structure cell (Rnst) and both A- and B-type ray neurons color-coded blue and orange, respectively. (E) Expression of posterior Hox genes in V6-derived rays. (F) Summary of NT identity of rays in wildtype (top left), egl-5 (top right) and mab-5 (bottom left) null mutants, and in mab-5 gain-of-function (gof) mutants (bottom right).

Figure 4.. Hox genes promote cell migration in the C. elegans nervous system.

(A) Starting position of the QR (anteriorly polarized) and QL (posteriorly polarized) neuroblasts between V5 and V6 at L1 stage. (B) Summary of QR.x/QL.x neuroblast migration in wildtype (top) and in lin-39 and mab-5 null mutants (bottom). (C) Migration defects in ceh-13 null mutants and depiction of opposing gradients of MIG-13 (anterior) and MAB-5 (posterior) that guide the migration of QR.X and QL.X. (D) Summary of HSN migration path in wildtype (left) and egl-5 null mutants (right).

Figure 5.. Hox expression in the mature C. elegans nervous system.

(A) Anatomy of the mature C. elegans nervous system. (B) Expression matrix of all 6 Hox genes (rows) in every neuron (columns) in the mature nervous system, ordered from anterior to posterior. Left-right and dorsal-ventral pairs of neurons are merged into one column when Hox gene expression is identical. Matrices are broken into the anatomical groups in A. *ceh-13 expression pattern is inferred from data in [101]; single-cell expression pattern is pending for this gene.

Figure 6.. Hox genes control neuronal terminal identity.

(A) (Top) Schematic of mature C. elegans with color-coded motor neurons and TRNs. Text label colors of motor neuron classes correspond to circles/cell bodies on the ventral surface of the animal. (Bottom) Hox expression domains are indicated with color code that is consistent with previous figures. (B) Schematic depicting anterior (CEH-13) and posterior (EGL-5) Hox genes collaborating with A/PLM terminal selector MEC-3 in sensory neurons to determine neuronal terminal identity. (C) Midbody (LIN-39, MAB-5) and posterior (EGL-5) Hox genes collaborate with UNC-3 to co-activate terminal identity genes in ventral cord motor neurons. (D) Midbody Hox genes and UNC-3 operate in a positive feedforward loop (FFL) to ensure robust expression of terminal identity genes in midbody motor neurons. (E) Hox (LIN-39) expression is maintained in motor neurons throughout life via positive autoregulation, which is balanced by negative UNC-3 feedback.