Endoplasmic reticulum (ER) remodeling is vital for cellular organization. ER-phagy, a selective autophagy targeting ER, plays an important role in maintaining ER morphology and function. The FAM134 protein family, including FAM134A, FAM134B, and FAM134C, mediates ER-phagy. While FAM134B mutations are linked to hereditary sensory and autonomic neuropathy in humans, the physiological role of the other FAM134 proteins remains unknown. To address this, we investigated the roles of FAM134 proteins using single and combined knockouts (KOs) in mice. Single KO in young mice showed no major phenotypes, but combined Fam134b and Fam134c deletion (Fam134b/cdKO) led to rapid neuromuscular and somatosensory degeneration, resulting in premature death. Fam134b/cdKO mice show rapid loss of motor and sensory axons in the peripheral nervous system. Long axons from Fam134b/cdKO mice exhibited expanded tubular ER with a transverse ladder-like appearance, whereas no obvious abnormalities were observed in cortical ER. Our study unveils critical roles of FAM134C and FAM134B in the formation of tubular ER network in axons of both motor and sensory neurons.