Nolz1 is induced by retinoid signals and controls motoneuron subtype identity through distinct repressor activities

Abstract

The acquisition and maintenance of final neuronal identity depends in part upon the implementation of fate-specification programs in postmitotic neurons; however, the mechanisms involved remain unclear. In the developing spinal cord, retinoic acid (RA) signaling pathways specify the columnar and divisional identities of postmitotic motoneurons (MNs). Here we show that RA signals induce expression of the NET transcriptional regulator Nolz1 in differentiated chick MNs, where it regulates the progressive specification of prospective Lim3-negative motor columns. Nolz1 controls the initial formation of forelimb and thoracic Lim3-negative motor columns by downregulating Lim3 expression and maintaining the expression of key homeodomain proteins necessary for MN identity and survival. At forelimb levels, Nolz1 specifies lateral motor column (LMC) identity by inducing the expression of the postmitotic LMC determinant Hoxc6, and implements the partial specification of lateral LMC identity through Lim1 induction. The specificity of Nolz1 function depends upon distinct repressor activities that require, in part, the modulatory activity of Grg5, an atypical member of the Gro-TLE family of co-repressors. Thus, RA signals regulate diverse events in MN subtype specification by inducing the expression of a key transcriptional regulator that controls multiple developmental pathways via functionally distinct repressor complexes.

Evolution of the NET (NocA, Nlz, Elbow, TLP-1) protein family in metazoans: insights from expression data and phylogenetic analysis

“…2c). This motif was previously named ‘Groucho-binding domain’, but recent data indicates that is not the domain required for the interaction between NET and Groucho/TLE proteins, at least not in vertebrates15181921. Finally, the previously described LP and PY domains21 were only found in vertebrates (Fig.…”

“…Accordingly, NET family members are known to repress Wnt and TGF-β mediated transcription212631, which are important signalling pathways expressed in all major extant metazoan lineages323334. Moreover, NET members interact with Groucho/TLE co-repressors7121518192126, which are found in all metazoan organisms35. These multiple interactions suggest that these families could co-operate in the embryonic development of most animals, explaining the conservation of the NET family across different taxonomic groups.…”

“…Vertebrates have two NET family members, the ZNF703 (also known as Nlz1) and ZNF503 (also known as Nlz2) paralogous proteins, which were first described in zebrafish1112. Studies on zebrafish, chicken and mouse have demonstrated that these proteins are widely expressed during embryogenesis in the brain, spinal cord, face, limbs and somites and participate in developmental processes that include optic fissure closure during eye development13, limb formation14, motoneuron identity specification15, hindbrain patterning111216171819 and striatum development1620. Although the expression of the two NET members during embryonic development in humans remain uncharacterized, we have previously shown that ZNF703 is expressed ubiquitously in human adult tissues21.…”

“…Several studies have shown that NET proteins function as transcription repressors1518192126 and are unlikely to directly bind DNA1. Moreover, the NET proteins interact with known players of the repression process in different species, such as Groucho family corepressors71215192126 and class I histone deacetylases HDAC1 and HDAC21218.…”

“…Moreover, the NET proteins interact with known players of the repression process in different species, such as Groucho family corepressors71215192126 and class I histone deacetylases HDAC1 and HDAC21218. It was recently shown that ZNF703 can repress TGFBR2 (transforming growth factor β receptor II) and E-cadherin expression226 as well as human TGF-β and TCF/β-catenin-mediated transcription2126.…”