Teashirt1 (Tshz1) is essential for the development, survival and function of hypoglossal and phrenic motor neurons

Abstract

Feeding and breathing are essential motor functions and rely on the activity of hypoglossal and phrenic motor neurons that innervate the tongue and diaphragm, respectively. Little is known about the genetic programs that control the development of these neuronal subtypes. The transcription factor Tshz1 is strongly and persistently expressed in developing hypoglossal and phrenic motor neurons. We used conditional mutation of Tshz1 in the progenitor zone of motor neurons (Tshz1MNΔ) to show that Tshz1 is essential for survival and function of hypoglossal and phrenic motor neurons. Hypoglossal and phrenic motor neurons are born in correct numbers, but many die between embryonic day 13.5 and 14.5 in Tshz1MNΔ mutant mice. In addition, innervation and electrophysiological properties of phrenic and hypoglossal motor neurons are altered. Severe feeding and breathing problems accompany this developmental deficit. Although motor neuron survival can be rescued by elimination of the pro-apoptotic factor Bax, innervation, feeding and breathing defects persist in Bax−/−; Tshz1MNΔ mutants. We conclude that Tshz1 is an essential transcription factor for the development and physiological function of phrenic and hypoglossal motor neurons.

Coordinated cadherin functions sculpt respiratory motor circuit connectivity

“…Unlike the majority of other MN subtypes, they largely eschew propriospinal inputs and instead integrate medullary inputs to produce robust respiratory activity ( Wu et al, 2017 ). The transcriptional programs that define molecular features of phrenic MNs which distinguish them from other MN populations during development are beginning to emerge ( Chaimowicz et al, 2019 ; Machado et al, 2014 ; Philippidou et al, 2012 ; Vagnozzi et al, 2020 ). Phrenic-specific transcription factors (TFs) deploy molecular programs that establish their unique morphology and stereotyped position, but whether these features of their identity contribute to their selective connectivity with excitatory premotor respiratory populations is not well understood.…”

Coordinated cadherin functions sculpt respiratory motor circuit connectivity

“…Unlike the majority of other MN subtypes, they largely eschew propriospinal inputs and instead integrate medullary inputs to produce robust respiratory activity (Wu et al, 2017). The transcriptional programs that define molecular features of phrenic MNs which distinguish them from other MN populations during development are beginning to emerge (Chaimowicz et al, 2019; Machado et al, 2014; Philippidou et al, 2012; Vagnozzi et al, 2020). Phrenic-specific transcription factors (TFs) deploy molecular programs that establish their unique morphology and stereotyped position, but whether these features of their identity contribute to their selective connectivity with excitatory premotor respiratory populations is not well understood.…”

Multiple Molecular Pathways Are Influenced by Progranulin in a Neuronal Cell Model–A Parallel Omics Approach

“…Expression of GAP-43, and SLC18A3 cells were unchanged between control and NSC-34/hPGRN cells but were decreased in NSC-34/shPGRN, Note the presence of genes associated with neurotransmission, cytoskeletal organization, and congenital neurological disorders. Among genes that showed the greatest fold down-regulation in NSC-34/shPGRN cells compared to NSC-34/hPGRN cells were several associated with neurotransmission (dopamine decarboxylase, vesicular GABA transporter, alpha-2 adrenergic receptor) (Azzouz et al, 2002;Bucheler et al, 2002;Johnson et al, 2003), cytoskeletal organization (Stathmin 2, FGD2, SRGAP3) (Endris et al, 2002;Budhachandra et al, 2008;Hayakawa et al, 2008;Carlson et al, 2011;Klim et al, 2019) and RNA-binding proteins with roles in neuron development, survival, or congenital motor disorders (IGF2BP1, TSHZ1, GLE1) (Nousiainen et al, 2008;Gaynes et al, 2015;Zhang et al, 2018;Chaimowicz et al, 2019). further supporting a role for PGRN in supporting neuronlike structural differentiation in NSC-34 cells.…”