Insm1 (IA-1) is an essential component of the regulatory network that specifies monoaminergic neuronal phenotypes in the vertebrate hindbrain

Abstract

Monoaminergic neurons include the physiologically important central serotonergic and noradrenergic subtypes. Here, we identify the zinc-finger transcription factor, Insm1, as a crucial mediator of the differentiation of both subtypes, and in particular the acquisition of their neurotransmitter phenotype. Insm1 is expressed in hindbrain progenitors of monoaminergic neurons as they exit the cell cycle, in a pattern that partially overlaps with the expression of the proneural factor Ascl1. Consistent with this, a conserved cis-regulatory sequence associated with Insm1 is bound by Ascl1 in the hindbrain, and Ascl1 is essential for the expression of Insm1 in the ventral hindbrain. In Insm1-null mutant mice, the expression of the serotonergic fate determinants Pet1, Lmx1b and Gata2 is markedly downregulated. Nevertheless, serotonergic precursors begin to differentiate in Insm1 mutants, but fail to produce serotonin because of a failure to activate expression of tryptophan hydroxylase 2 (Tph2), the key enzyme of serotonin biosynthesis. We find that both Insm1 and Ascl1 coordinately specify Tph2 expression. In brainstem noradrenergic centres of Insm1 mutants, expression of tyrosine hydroxylase is delayed in the locus coeruleus and is markedly deficient in the medullary noradrenergic nuclei. However, Insm1 is dispensable for the expression of a second key noradrenergic biosynthetic enzyme, dopamine β-hydroxylase, which is instead regulated by Ascl1. Thus, Insm1 regulates the synthesis of distinct monoaminergic neurotransmitters by acting combinatorially with, or independently of, Ascl1 in specific monoaminergic populations.

Distinct populations of GABAergic neurons in mouse rhombomere 1 express but do not require the homeodomain transcription factor PITX2

“…LMX1B is a LIM homeodomain transcription factor involved in initiation and maintenance of the isthmic organizer and is important for midbrain and hindbrain patterning (Jacob et al, 2009; Matsunaga et al, 2002; Mishima et al, 2009). Lmx1b is expressed in the principal sensory nucleus of the trigeminal nerve, the Kölliker-Fuse nucleus, the dorsal raphe, and the parabrachial nuclei (Dai et al, 2008; Jacob et al, 2009; Matsunaga et al, 2002; Prakash et al, 2009; Zervas et al, 2005). LMX1B is also required for the differentiation of midbrain dopaminergic neurons and hindbrain serotonergic neurons (Ding et al, 2003; Jacob et al, 2009).…”

Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes

“…It is also essential for the neuronal phenotype in some brain cells (43,44). INSM1 is a transcriptional repressor, blocking expression of the Notch signaling HES1 and REST (see below) by binding to its corepressors RCOR1 and RCOR2, thus maintaining ASCL1 expression (45,46).…”

Genetic Models of Serotonin (5‐HT) Depletion: What do They Tell Us About the Developmental Role of 5‐HT?

“…A first set of transcription factors, Nkx2.2, Nkx2.9, and Ascl1, are required to generate 5-HT precursors in the raphe between embryonic days 8 and 10, in mice. A second set of transcription factors, GATA2, GATA3, Insm1, Fox A2, Lmx1b, and Pet1, are required for 5-HT subtype selection and 5-HT neuron terminal differentiation between E10 and E12 (Cordes, 2005;Jacob et al, 2007;Jacob et al, 2009). Other transcription factors, such as Phox2B and Hoxb1, are involved in repressing the 5-HT phenotype of the precursors in specific brainstem regions (Pattyn et al, 2004).…”