An emerging role for prdm family genes in dorsoventral patterning of the vertebrate nervous system

Abstract

The embryonic vertebrate neural tube is divided along its dorsoventral (DV) axis into eleven molecularly discrete progenitor domains. Each of these domains gives rise to distinct neuronal cell types; the ventral-most six domains contribute to motor circuits, while the five dorsal domains contribute to sensory circuits. Following the initial neurogenesis step, these domains also generate glial cell types—either astrocytes or oligodendrocytes. This DV pattern is initiated by two morphogens—Sonic Hedgehog released from notochord and floor plate and Bone Morphogenetic Protein produced in the roof plate—that act in concentration gradients to induce expression of genes along the DV axis. Subsequently, these DV-restricted genes cooperate to define progenitor domains and to control neuronal cell fate specification and differentiation in each domain. Many genes involved in this process have been identified, but significant gaps remain in our understanding of the underlying genetic program. Here we review recent work identifying members of the Prdm gene family as novel regulators of DV patterning in the neural tube. Many Prdm proteins regulate transcription by controlling histone modifications (either via intrinsic histone methyltransferase activity, or by recruiting histone modifying enzymes). Prdm genes are expressed in spatially restricted domains along the DV axis of the neural tube and play important roles in the specification of progenitor domains, as well as in the subsequent differentiation of motor neurons and various types of interneurons. Strikingly, Prdm proteins appear to function by binding to, and modulating the activity of, other transcription factors (particularly bHLH proteins). The identity of key transcription factors in DV patterning of the neural tube has been elucidated previously (e.g. the nkx, bHLH and pax families), but it now appears that an additional family is also required and that it acts in a potentially novel manner.

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

“…In the p419 mutant line in which the C1 turning angle of the startle response is dramatically increased (165% of wild type siblings; Table 1 and Fig 1L–1P and S3 Video ), we identified a missense mutation in the coding sequence of PR domain containing 12b ( prdm12b ). Prdm proteins are transcription factors, and several family members have been shown to play roles in nervous system development [ 43 ]. Zebrafish prdm12b was previously identified in a screen for genes that express in the nervous system [ 44 ].…”

Rostrocaudal patterning and neural crest differentiation of human pre-neural spinal cord progenitors in vitro

“…Analysis of lateral motor column (LMC; FOXP1), dorsal interneuron/lateral motor column marker (LHX1) and medial motor column markers (MMC; LHX3) found that all PNP conditions preferentially generated LHX1 + / TUJ + cells although did not express ISL1 (Figure 8B,D). The prescense of LHX1 + /ISL1 − positive neurons, suggests neurons may be lateral LMC (LHX1 + /ISL2 + ), interneurons of the p2-dp2 domains or medial LMC which no longer express early motor neuron markers (Francius and Clotman, 2014, Zannino and Sagerström, 2015) (Figure 8B). Few cells were found to express LHX3 indicating cells preferentially differntate MMC motor neurons (Figure 8C).…”

A forward genetic screen identifies Dolk as a regulator of startle magnitude through the potassium channel subunit Kv1.1

“…Prdm proteins are transcription factors, and several family members have been shown to play roles in nervous system development [43]. Zebrafish prdm12b was previously identified in a screen for genes that express in the nervous system [44].…”