Figure 3. Molecular organization of spinal neurons.

(a) During embryonic development, spinal interneurons are derived from 13 progenitor domains (including the late born dILa and dILb domains). Highlighted are the pMN, p1, and p2 domains. After neurogenesis, cells migrate to their final settling positions [2].

(b) The p1 domain generates V1 interneurons, which express En1. V1 interneurons settle throughout the ventral horn. The majority of V1 interneurons can be divided into 4 clades, expressing either Sp8, Pou6f2, FoxP2, or MafA. V1 clades can be further divided into many subtypes based on combinatorial expression of additional transcription factors. These additional transcriptional divisions often correspond to spatial divisions as well [32^••].

(c) The p2 domain generates V2a–V2d interneurons [2,55]. V2a interneurons are divided into a medial and lateral column based on Nfib and Zfhx3 expression. Each column comprises multiple transcriptionally distinct subtypes; however, the spatial locations of these subtypes have yet to be examined in detail [34^••].

(d) The pMN domain gives rise to motor neurons, which express Hb9 and settle in the ventral spinal cord. Motor neurons are organized into columns. While all motor neurons initially express Lhx3, only the MMC (Medial motor column) maintains its expression. The LMC (Lateral motor column) expresses FoxP1. Within each column, motor neurons can be further divided into motor pools, each of which is spatially clustered and has a unique muscle target [10-12].

(e–g) Categories of neurons based on their rostrocaudal distribution. Constant: a population of neurons which are present throughout the length of the spinal cord. Limb: neurons which reside in the cervical and lumbar cord. Thoracic: neurons which are located in the thoracic cord. Gradient: neurons that are arrayed in a gradient along the cord.

(e) V1 interneuron clades are preserved across the rostrocaudal axis. However, V1 subtypes specific to limb segments or thoracic segments can be identified based on the expression of two transcription factors [38^••].

(f) V2a columns span the rostrocaudal axis. The composition of each column is a combination of Type I V2a interneurons (which maintain Chx10 expression) and Type II V2a interneurons (which downregulate Chx10). The ratio of the two types remains constant in the medial column. In the lateral column, the ratio is organized in a gradient manner which is dependent on spinal segment. Cervical segments are composed of primarily Type II V2a interneurons, while lumbar segments are primarily Type I V2a interneurons [34^••].

(g) The MMC, HMC (Hypaxial motor column), and LMC synapse onto axial, intercostal, and limb muscles, respectively. The MMC spans the spinal cord, while the HMC and LMC are segment specific. Motor pools are segmentally organized as well [10-12]. Example LMC motor pools are shown (MMC and HMC pools are not shown). Motor pools generally span a few segments [10,12].